The Toxicologist - Society of Toxicology

More documents

Recommendations

Info

1820 RAT LIVER MICROSOMES ENANTIOSELECTIVELY CATALYZE THE FORMATION OF HYDROXYLATED METABOLITES OF 2, 2’, 3, 3’, 6, 6’- HEXACHLOROBIPHENYL (PCB136). I. Kania-Korwel 1 , M. W. Duffel 2 , S. Bandiera 3 and H. Lehmler 1 . 1 Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA, 2 Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA and 3 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. Chiral PCB congeners such as PCB136 undergo enantiomeric enrichment in vivo. The biotransformation processes responsible for this enantiomeric enrichment are still poorly understood. A series of metabolism studies was performed to test the hypothesis that metabolism of PCB136 is enantioselective and isoform-dependent in liver microsomes from rats treated with phenobarbital (PB, CYP2B induced), dexamethasone (DEX, CYP3A induced) or corn oil (CO). Incubations of all three types of microsomes with racemic PCB136 (50 μM) resulted in the time-dependent formation of hydroxylated metabolites. Microsomes from PB-treated animals generated the highest amount of metabolites, followed by microsomes from DEX and CO- treated rats. The major metabolite in all preparations was 5-OH-PCB 136 and the rank order was 5-OH-PCB 136 > 4-OH-PCB136 > 4,5-diOH-PCB136. However, the relative contribution of 4-OH-PCB136 depended on the microsomal preparation and increased in microsomes from DEX and CO-treated rats. Carbon monoxide inhibited the formation of metabolites, which is consistent with the involvement of cytochrome P450 isoforms in the metabolism of PCB136. Incubation of microsomal preparations from both PB- and DEX-treated rats with (+)-, (-)-, and racemic PCB 136 revealed no clear differences in metabolite profiles. Although no enantiomeric enrichment of PCB136 was observed, the second eluting atropisomers of 4-OH-PCB136 and 5-OH-PCB136 were slightly enriched in incubations with racemic PCB136. Incubations with pure PCB 136 atropisomers demonstrated that the second eluting atropisomers of both metabolites are formed from (+)-PCB136. Overall, these studies demonstrate the enantioselective and isoform-dependent formation of hydroxylated PCB 136 metabolites by cytochrome P450 enzymes (Supported by NIH ES017425). 1821 MYELOPEROXIDASE-MEDIATED BIOACTIVATION OF 5-HYDROXYTHIABENDAZOLE: A POSSIBLE MECHANISM BEHIND THE TOXICITIES ASSOCIATED WITH THIABENDAZOLE. J. Jamieson, E. Smith, D. Dalvie, G. Stevens and G. Yanochko. Pfizer, Inc., San Diego, CA. Thiabendazole (TBZ), an antihelminthic and antifungal agent, is associated with a host of adverse effects including nephrotoxicity, hepatotoxicity, and teratogenicity. Bioactivation of the primary metabolite of TBZ, 5-hydroxythiabendazole, has been proposed to yield a reactive intermediate. Here we show that this reactive intermediate can be generated by myeloperoxidase, a neutrophil-bourne peroxidase. Using a cell viability endpoint, we examined the toxicity of TBZ, 5OH-TBZ, and MPOgenerated metabolites in cell-based models including primary rat proximal tubule epithelial cells, NRK-52E rat proximal tubule cells, and H9C2 rat myocardial cells. Timecourse experiments with MPO showed complete turnover of 5OH-TBZ within 15 minutes and a dramatic leftward shift in dose-response curves after 12 hours. After a 24 hour exposure in vitro, the LC50 of this reactive intermediate was 22 ± 1μM compared to 117 ± 20μM from 5OH-TBZ alone, a greater than 5-fold decrease. LC50 values were equal in all cell types used. This toxicity can be completely rescued via incubation with rutin, an inhibitor of MPO. These results suggest that MPO-mediated biotransformation of 5OH-TBZ yields a reactive intermediate which may play a role in TBZ-induced toxicity. 1822 METABOLISM OF 2-HYDROXY-4- METHOXYBENZOPHENONE DEPENDS ON SPECIES AND SEX. C. Wegerski 1 , S. S. Auerbach 2 , J. M. Sanders 2 , M. Doyle-Eisele 1 and J. D. McDonald 1 . 1 Lovelace Respiratory Research Institute, Albuquerque, NM and 2 NTP/NIEHS, Research Triangle Park, NC. Metabolism and disposition studies of 2-Hydroxy-4-methoxybenzophenone (HMB) are being conducted to aid in interpretation of toxicology results and interspecies and sex extrapolation. To assess species and sex differences within rodents, in vivo studies were conducted by oral dose administration of 14C labeled HMB in male and female Sprague-Dawley rats and B6C3F1 mice. Urine samples were analyzed for HMB metabolites. To confirm these results and extend to human metab- 390 SOT 2011 ANNUAL MEETING olism, in vitro studies were conducted by incubating 14C HMB with male and female liver hepatocytes from Sprague-Dawley rats, B6C3F1 mice, and humans. Samples were analyzed by LC-RAD and/or LC-MS/MS. There were sex differences in the in vivo metabolism of HMB detected in urine between the male and female rat. The major metabolite in the female rat was not detected in the male rat. Similarly, the major metabolite in the male rat was a minor metabolite in the female rat. There were also species differences between the rat and mouse, with the major metabolite in the male mouse urine present only in trace quantities in the male rat urine. Both HMB and 2,4-dihydroxy-benzophenone, which were present in the male mouse and rat urine, were absent or in trace quantities in the female rat urine. Species and sex differences in HMB metabolism were also observed in isolated rat, mouse and human hepatocytes. Female rodent hepatocytes produced all HMB-derived metabolites present in males, as well as a few minor metabolites not evident in males. Male human hepatocytes produced 10 HMB-derived metabolites compared to 8 detected in female human hepatocytes. The metabolites detected in these studies were primarily glucuronide and sulfate conjugates, but some Phase I oxidative intermediate metabolites were also observed. The in vitro data indicate that the mouse is a closer metabolic match to humans than the rat. (Work conducted under NIEHS contract N01-ES-75562). 1823 THE IN VITRO METABOLISM OF METHYL AND PROPYL PARABENS IN HUMAN AND RAT. K. Choi, H. Joo, J. Campbell, M. Andersen and H. Clewell. The Hamner Institutes for Health Sciences, Research Triangle Park, NC. Parabens are antimicrobial preservatives widely used in cosmetic products and pharmaceuticals as well as in food and beverage processing. Methyl paraben (MP) and propyl paraben (PP) are the most predominantly used parabens. In mammals parabens are extensively hydrolyzed to p-hydroxy benzoic acid (pHBA) and further undergo phase II biotransformation via glucuronide, glycine and sulfate conjugation. However, their metabolism in humans has not been well characterized. We investigated the metabolism of MP and PP using subcellular fractions of various organs in human and rat. In human, pHBA was mainly produced in the liver, followed by the lung, skin, intestine and testis (for MP) or the intestine, kidney, lung, skin and testis (for PP). For MP in human, the velocities for pHBA production were 94.72±5.35 and 46.23±0.07 in liver microsomes and cytosol and 38.17±3.64 and 13.11±0.45 (nmol mg protein-1 min-1) in lung microsomes and cytosol, respectively. For PP, the velocities for the production of pHBA were 114.71±0.85 and 45.90±1.48 in liver microsomes and cytosol, 8.79±0.05 and 32.38±5.50 (nmol/mg protein/ min) in intestine microsomes and cytosol, respectively. In rat liver microsomes, the velocities for the production of pHBA with treatment of MP and PP were 106.14±2.55 and 104.15±4.88 and in rat liver cytosol 36.53±6.0 and 111.76±3.05 (nmol/mg protein/min), respectively. These metabolism data provide key parameters for PBPK models that support cross-species extrapolation of parabens exposures. 1824 PHASE II BIOTRANSFORMATION OF DI(2- EHTYLHEXYL) PHTHALATE IN HUMAN AND RAT. H. Joo 1 , K. Choi 1 , J. Grimes 1, 2 , T. O’Connell 1, 2 , R. Clewell 1 , J. Campbell 1 and H. Clewell 1 . 1 The Hamner Institutes for Health Sciences, Research Triangle Park, NC and 2 The UNC, Chapel Hill, NC. In this study we demonstrated that three metabolites of di(2-ethylhexyl) phthalate (DEHP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-OH-hexyl) phthalate (5-OH MEHP) and mono(2-ethyl-5-oxo-hexyl) phthalate (5-oxo MEHP), were metabolized via conjugation with glucuronic acid in pooled human liver (HLM) and rat liver microsomes (RLM). Production of MEHP-, 5-OH MEHPand 5-oxo MEHP glucuronide was measured by LC-ESI (-)/MS/MS. The metabolic rates in HLM and RLM were 37,460 ± 5,565 and 4,472 ± 206 for MEHP glucuronide, 102,229 ± 1,160 and 868 ± 3 for 5-OH MEHP glucuronide and 5,549 ± 350 and 920 ± 28 (AUC mg protein-1 min-1) for 5-oxo MEHP glucuronide, respectively. We also determined metabolic activities of 12 human uridine 5-diphosphoglucuronosyl transferase (UGT) isoforms (1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17) toward MEHP, 5-OH MEHP and 5-oxo MEHP. Among the 12 UGTs 1A3, 1A8, 1A10, 2B7 and 2B17 were major isoforms for MEHP glucuronide production, while 1A3, 1A7, 1A8, 1A9, 1A10 and 2B7 were mainly responsible for the production of 5-OH MEHP- and 5-oxo MEHP glucuronide. The percent total normalized rates (%TNR) were 84% for MEHP glucuronide by UGT2B7 and 80% and 85% for 5-OH MEHP- and 5oxo MEHP glucuronide by UGT1A9, respectively. Additionally, we developed a method to biosynthesize milligram quantities of MEHP glucuronide for use as a reference standard. These metabolism data are being used to support PBPK model evaluation of cross-species dosimetry and human interindividual variability for DEHP exposures.
1825 EFFECTS OF METABOLISM BY INTESTINAL MICROORGANISM ON PHARMACOKINETICS OF BAICALIN IN VIVO. T. Jeong, M. Kang, G. Ko, S. Yoo, H. Ha, M. Kong and D. Lee. Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea. Baicalin is an active ingredient of Scutellaria baicalensis Georgi. Scutellaria baicalensis is one of the most popular herbs used in Korea traditionally for treatment of inflammation, cardiovascular diseases, hypertension, and bacterial and viral infections. In this study, effects of intestinal microorganism on the pharmacokinetics of baicalin were determined in conventional and antibiotics-treated rats following p.o. administration with 100 mg/kg baicalin by using liquid chromatography/electrospray ionization mass spectrometry. The Tmax values of baicalin in conventional and antibiotics-treated rats were 4.00 and 3.60 hr, respectively. The AUC values were 51.76 and 26.42 μg×hr/ml. These results showed that the intestinal microorganism might have an important role in pharmacokinetics of baicalin. [Supported by a grant (09172KFDA996) from Korea Food & Drug Administration.] 1826 IMMUNOTOXIC EFFECTS OF ARBUTIN VIA METABOLISM BY INTESTINAL BACTERIA IN VITRO. M. Kang 1 , H. Ha 1 , H. Kim 2 , G. Ko 1 , S. Yoo 1 , D. Lee 1 , M. Kong 1 , Y. Ahn 3 , H. Jeong 2 and T. Jeong 1 . 1 Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea, 2 Pharmacy, Chungnam National University, Daejeon, Republic of Korea and 3 Yakult Co., Yongin, Republic of Korea. A possible role of metabolism by intestinal bacteria in arbutin-induced toxicity was investigated in spleen cell cultures from mice. Following an incubation of arbutin with intestinal bacteria for 24 h, its aglycone hydroquinone could be produced in the bacterial culture media and detected by an HPLC. When the toxicity was compared in the spleen cell cultures, hydroquinone was more toxic than the parent arbutin, indicating that metabolic activation might be required in arbutin-induced toxicity. After arbutin was incubated with intestinal bacteria for 24 h, ability of the incubate to suppress LPS and Con A mitogenicity was tested. As results, the incubate with intestinal bacteria was more toxic when compared to arbutin control. The present results indicate that the current system might be applied for assessing the possible role of metabolism by intestinal bacteria in chemical-induced toxicity in spleen cell cultures of mice. (Supported by a grant (09172KFDA996) from Korea Food & Drug Administration.) 1827 ROLE OF METABOLISM BY INTESTINAL BACTERIA IN GENIPOSIDE-INDUCED TOXICITY IN MAMMALIAN CELL CULTURES. M. Kong 1 , H. Ha 1 , H. Kim 2 , G. Ko 1 , S. Yoo 1 , D. Lee 1 , M. Kang 1 , H. Jeong 2 and T. Jeong 1 . 1 Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea and 2 Pharmacy, Chungnam National University, Daejeon, Republic of Korea. A possible role of metabolism by intestinal bacteria in geniposide-induced toxicity was investigated in mammalian cell cultures. Following an incubation of geniposide with intestinal bacteria for 24 h, it was estimated that geniposide was metabolized to genipin in the bacterial culture media. When the toxicity was compared in the HepG2 cell lines, genipin was more toxic than the parent geniposide, indicating that metabolic activation might be required in geniposide-induced toxicity. After geniposide was incubated with intestinal bacteria for 24 h, cytotoxicity was highly increased when compared to geniposide control. The present results indicate that the current system might be useful for assessing the possible role of bacterial metabolism in mammalian cell cultures. (Supported by a grant (09172KFDA996) from Korea Food & Drug Administration in 2010.) 1828 METABOLIC CONVERSION OF AFLATOXIN B2 TO AFLATOXIN B1 IN DUCKS. A. Poapolathep 1 , S. Poapolathep 1 , S. Isariyodom 3 , K. Imsilp 1 , N. Klangkaew 1 , Y. Sugita-Konishi 4 and S. Kumagai 2 . 1 Department of Pharmacology, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, Thailand, 2 Research Center for Food Safety, University of Tokyo, Tokyo, Japan, 3 Department of Animal Husbandry, Faculty of Agriculture, Kasetsart University, Bangkok, Thailand and 4 Division of Microbiology, National Institute of Health Sciences, Tokyo, Japan. Our previous research revealed that AFB2 can be converted to AFB1 by using postmitochondrial (S-9) fraction of liver from six different animal species with different magnitudes. Among those, duck livers were more susceptible to the AFB2-to-AFB1 conversion. This study was aimed to investigate this AFB2-to-AFB1 conversion in whole ducks. We, thus, administered AFB2 to ducks either intravenously (IV) or orally (PO) at a dosage of 1 mg/kg body weight. Plasma and liver were collected and analyzed for both AFB2 and AFB1 using liquid chromatography/tandem mass spectrometry (LC/MS/MS). The AFB2 was detected in plasma for up to 12h and 8h whereas AFB1 was up to 1h and 30 min after IV and PO, respectively. Both aflatoxins were also found in duck livers. This in vivo study confirms that AFB2 can be metabolized to AFB1 in ducks as those found in the in vitro study. 1829 THIOETHER METABOLITES OF 3, 4- METHYLENEDIOXYMETHAMPHETAMINE ARE POTENT INHIBITORS OF THE HUMAN SEROTONIN TRANSPORTER (HSERT). L. E. Lizarraga, J. Herndon, S. S. Lau and T. J. Monks. Pharmacology/Toxicology, University of Arizona-College of Pharmacy, Tucson, AZ. 3,4-Methylenedioxymethamphetamine (MDMA, ecstacy) is a ring substituted amphetamine derivative with potent stimulant properties. MDMA long-term serotonergic neurotoxicity manifests as prolonged depletion in serotonin (5-HT) and structural damage to 5-HT axons. The former effect is likely mediated via the ability of MDMA to inhibit 5-HT uptake via the 5-HT transporter (SERT), since fluoxetine, a selective 5-HT reuptake inhibitor, protects against MDMA-induced ROS generation and neurotoxicity. The basis for the structural damage remains unclear. Metabolism of MDMA to N-methyl-α-methyldopamine (N-Me-α-MeDA), followed by oxidation and adduction of the corresponsing ortho-quinone with glutathione (GSH) leads to the formation of 5-(glutathion-S-yl)-N-Me-α-MeDA and 2,5-bis(GSyl)-N-Me-α-MeDA. Thioether conjugates of N-Me-α-MeDA are neurotoxic, however, their mechanism of action remains unclear. We now investigated the effect of GSH and N-acetylcysteine (NAC) conjugates of N-Me-α-MeDA on SERT function. Human embryonic kidney cells (HEK) were transiently transfected with hSERT and incubated with [3H]-5-HT to measure transport via SERT. We confirmed expression of SERT protein by western blot analysis of HEK-SERT. The cellular uptake of [3H]-5-HT into hSERT-expressing cells was rapid and continued to accumulate, reaching maximal uptake after 50 minutes. Km and Vmax values for specific [3H]5-HT uptake were determined to be 7.9 μM and 0.23 μM/min, respectively. The inhibitory effect of MDMA metabolites on SERT function was determined by measuring uptake of [3H]5-HT with varying concentrations of the metabolites. N-Me-α-MeDA thioether metabolites inhibited [3H]5-HT uptake into HEK-SERT cells, and to a greater extend than the parent drug, MDMA. The results are consistent with the hypothesis that MDMA-induced serotonergic neurotoxicity involves metabolism-mediated modulation of SERT function. We are currently investigating MDMA effects in SERT-KO rats to further address the role of SERT in MDMA-mediated neurotoxicity. 1830 METABOLISM OF 2, 2’, 3, 3’, 6, 6’- HEXACHLOROBIPHENYL (PCB136) IN PRECISION- CUT RAT LIVER SLICES. X. Wu 1 , K. Dammanahalli 2 , M. Duffel 2 and H. Lehmler 1 . 1 Occupational and Environmental Health, The University of Iowa, Iowa City, IA and 2 Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, IA. Biotransformation of 2,2’,3,3’,6,6’-hexachlorobiphenyl (PCB136) may contribute to the developmental toxicity of polychlorinated biphenyls (PCBs) through the formation of neurotoxic metabolites. Here we investigate the hypothesis that PCB136 can be enantioselectively metabolized to hydroxylated PCB136 (OH-PCB136) metabolites in precision-cut rat liver slices. Liver tissue slices (250 μm thickness, 8 mm diameter) were obtained from 8-week old female or male Sprague-Dawley rats treated for three or four consecutive days with either Phenobarbital (PB, CYP2B inducer) or dexamethasone (DEX, CYP3A inducer). Tissue slices were incubated for 2 h with Krebs-Henseleit buffer (pH 7.4) containing 5 μM PCB136. Lactate dehydrogenase release from the tissue slices to the medium was 12.8% indicating the viability of the liver slices during the incubation. Levels of PCB136 and its hydroxylated metabolites in tissue slices and medium were determined by gas chromatography using a 63Ni μ-ECD detector. PCB136 levels in medium were 3~7 times higher compared to tissue slice levels after incubation. Less than 10% of PCB136 was biotransformed to its hydroxylated metabolites. Levels of 5-OH PCB136 were 2-times higher in tissue slices from PB- versus DEX-treated rats. The metabolite pattern in PB- and DEX-treated rats was similar and followed the rank order 5-OH-PCB136 >> 4-OH-PCB136 > 4,5-diOH-PCB136. The enantiomeric fraction (EF) of PCB136 in medium samples was 0.50, while the EF value in the liver slices (EF = 0.48 to 0.49) displayed a slight enrichment of (-)-PCB136 after 2 h incubation. No gender-specific differences in the metabolite profile or the EF values were observed. Overall, the metabolite pattern of PCB136 in rat liver slices was SOT 2011 ANNUAL MEETING 391
Page 1 and 2:
The Toxicologist Supplement to Toxi
Page 3 and 4:
The Toxicologist Supplement to Toxi
Page 5 and 6:
1 BIODEGRADABLE MATERIALS FOR TISSU
Page 7 and 8:
that genetic toxicology data are ge
Page 9 and 10:
well-orchestrated lung inflammation
Page 11 and 12:
scribed in the literature. We have
Page 13 and 14:
years ago). We will illustrate how
Page 15 and 16:
involved in the biodegradation proc
Page 17 and 18:
stem cells but rather a treatment i
Page 19 and 20:
additional compound showed agreemen
Page 21 and 22:
82 COMPARISON OF 3H-THYMIDINE INCOR
Page 23 and 24:
irritants. While in practice these
Page 25 and 26:
alleles are especially vulnerable t
Page 27 and 28:
109 CD4+ T CELL INTRINSIC TNF RECEP
Page 29 and 30:
118 TO STUDY THE SIGNAL TRANSDUCTIO
Page 31 and 32:
PAHs, such as dioxins, are prevalen
Page 33 and 34:
containing substituents and/or hydr
Page 35 and 36:
146 COMPUTATIONAL MODELING FOR QT P
Page 37 and 38:
suggest that the combination of too
Page 39 and 40:
164 TRANSLOCATOR PROTEIN (18 KDA) (
Page 41 and 42:
function as a metal binding protein
Page 43 and 44:
laboratory has demonstrated that NR
Page 45 and 46:
known. The aim of this study was to
Page 47 and 48:
from 5 to 28 days in duration) in e
Page 49 and 50:
positive cells, caspase-3 activatio
Page 51 and 52:
creased level in the 46 kDa preproe
Page 53 and 54:
invasiveness at concentrations repr
Page 55 and 56:
thracene (DMBA,50 μg in acetone, a
Page 57 and 58:
247 CO-CARCINOGENESIS OF N, N- DIET
Page 59 and 60:
sponds to the endosomal dsRNA that
Page 61 and 62:
ODD in both WT (maximum 177% of con
Page 63 and 64:
Lastly, using p53siRNA cells, p53 w
Page 65 and 66:
its receptor Mpl to exert its funct
Page 67 and 68:
294 LOW LEVEL OF LEAD CAN INDUCE PH
Page 69 and 70:
lunar surface presented potential h
Page 71 and 72:
lar about cellular export mechanism
Page 73 and 74:
DNA in the kidney medulla, grandula
Page 75 and 76:
5.00 and 7.50 mg/kg/day by oral gav
Page 77 and 78:
events and carcinogenesis. Here we
Page 79 and 80:
tinization of cells of the hair fol
Page 81 and 82:
358 CHARACTERIZATION OF GENOME-WIDE
Page 83 and 84:
RNAi were also performed to identif
Page 85 and 86:
376 A FUNCTIONAL CROSSTALK BETWEEN
Page 87 and 88:
UGT1A gene induction, while this re
Page 89 and 90:
tivity, specifically peroxisome pro
Page 91 and 92:
and cytotoxic effects; however, its
Page 93 and 94:
histone deacetylase that is necessa
Page 95 and 96:
ment. Paradoxically, buthionine sul
Page 97 and 98:
drug leflunomide and its major (A77
Page 99 and 100:
442 GENE EXPRESSION AND MORPHOLOGIC
Page 101 and 102:
451 INHIBITION OF THE MITOCHONDRIAL
Page 103 and 104:
460 SULFORAPHANE PREVENTS ACETAMINO
Page 105 and 106:
drophilic/lipophilic balance. Other
Page 107 and 108:
pharmacokinetic and toxicological p
Page 109 and 110:
489 USE OF ‘OMICS DATA TO IMPROVE
Page 111 and 112:
498 APPLICATION OF AGE-SPECIFIC ADJ
Page 113 and 114:
507 A DOSE VOLUME TOLERABILITY STUD
Page 115 and 116:
involved the use of an acute inflam
Page 117 and 118:
sorption in the gastrointestinal (G
Page 119 and 120:
(ABC) transporters actively transpo
Page 121 and 122:
545 BEHAVIORAL EFFECTS OF REPIN IN
Page 123 and 124:
a blood pressure phenotype that res
Page 125 and 126:
and inhalation exposure system that
Page 127 and 128:
and lethality associated with these
Page 129 and 130:
position, on vascular reactivity an
Page 131 and 132:
therefore more accurate and reprodu
Page 133 and 134:
commercial chrysotile product that
Page 135 and 136:
elative to their controls. ST-depre
Page 137 and 138:
ats. The majority of the studies fo
Page 139 and 140:
in the China Jintan Child Cohort St
Page 141 and 142:
corneum thickness, cellular epiderm
Page 143 and 144:
645 EVALUATION OF THE IN VITRO EPIS
Page 145 and 146:
654 TCDD ADSORBED ONTO NATURAL AND
Page 147 and 148:
tion revealed no test article-relat
Page 149 and 150:
671 INFLAMMATION AND TISSUE DAMAGE
Page 151 and 152:
model, ethanol was found to inhibit
Page 153 and 154:
689 ENHANCED SUPPRESSIVE FUNCTION O
Page 155 and 156:
NAC + LPS yielded different levels
Page 157 and 158:
707 LIFE-STAGE PBPK MODELS FOR MULT
Page 159 and 160:
downstream of the apical endpoint o
Page 161 and 162:
726 UPDATED ALUMINUM PHARMACOKINETI
Page 163 and 164:
global parameter sensitivity analys
Page 165 and 166:
and renal inflammation induced by 2
Page 167 and 168:
754 PLASMA, URINE, AND TISSUE CONCE
Page 169 and 170:
cently characterized transporter OA
Page 171 and 172:
exposure system was developed from
Page 173 and 174:
lood cell mass and decrease in urin
Page 175 and 176:
practical alternatives to MC in non
Page 177 and 178:
imals dosed with 167 mg/kg THU alon
Page 179 and 180:
and organ weights, clinical signs a
Page 181 and 182:
yet is induced in most bladder and
Page 183 and 184:
830 RISK ASSESSMENT OF THE SPILL: C
Page 185 and 186:
knowledgebase creation. Results are
Page 187 and 188:
852 UNDERSTANDING STRUCTURAL AND PH
Page 189 and 190:
for integrating epidemiology and an
Page 191 and 192:
motor activity, including age of th
Page 193 and 194:
y partial purification of urine (fr
Page 195 and 196:
pacity for self-renewal and may dif
Page 197 and 198:
sue. The depth of our analysis led
Page 199 and 200:
910 IMPLEMENTING CALIFORNIA’S GRE
Page 201 and 202:
concentrations in six tissues and b
Page 203 and 204:
934 THE FDA’S LIVER TOXICITY KNOW
Page 205 and 206:
943 GENOME-WIDE DNA METHYLATION DIF
Page 207 and 208:
membrane localization and subsequen
Page 209 and 210:
trols, respectively. Subtoxic and t
Page 211 and 212:
survival using both smoking regimes
Page 213 and 214:
as non-, weak, moderate, or strong
Page 215 and 216:
988 NNK-INDUCED CYTOKINE ALTERATION
Page 217 and 218:
group (one-way ANOVA, p90 % viabili
Page 219 and 220:
ered as an organ involved in xenobi
Page 221 and 222:
Transport of CPZ across the Caco-2
Page 223 and 224:
estrous cycle and sexual behavior d
Page 225 and 226:
mRNA expression levels. Collectivel
Page 227 and 228:
1043 THE EFFECTS OF ENDOCRINE DISRU
Page 229 and 230:
1052 MONO-2-ETHYLHEXYL PHTHALATE IN
Page 231 and 232:
Results: MC was variable within and
Page 233 and 234:
UtSMCs. Phosphorylation of FoxO1 wa
Page 235 and 236:
nonpregnant and pregnant diabetic m
Page 237 and 238:
1089 PFOA-INDUCED LIVER EFFECTS IN
Page 239 and 240:
events in the liver. AZD9056 was ev
Page 241 and 242:
The peppermint oil caused a concent
Page 243 and 244:
OA did not affect food consumption.
Page 245 and 246:
1126 PERSISTENT DEVELOPMENTAL ARYLH
Page 247 and 248:
1135 BACH2 BINDING TO Prdm1 AS A ME
Page 249 and 250:
The purpose of this project was to
Page 251 and 252:
one marrow. Since Chk1 is an attrac
Page 253 and 254:
1163 THE MRNA AND MIRNA PROFILE OF
Page 255 and 256:
have now compared the IC50 values b
Page 257 and 258:
1181 ELUCIDATION OF FACTORS DETERMI
Page 259 and 260:
enced by pre-exposure to cigarette
Page 261 and 262:
if abnormal PF was associated with
Page 263 and 264:
weight (P=0.016) and small for gest
Page 265 and 266:
portant cause of death, compared to
Page 267 and 268:
posure groups. However, the differe
Page 269 and 270:
Naphthalene is routinely analyzed i
Page 271 and 272:
1245 SEASONAL CHARACTERIZATION OF H
Page 273 and 274:
1255 URINARY T, T MUCONIC ACID LEVE
Page 275 and 276:
modating a reliable data evaluation
Page 277 and 278:
enzoquinone generate ROS and arylat
Page 279 and 280:
teins (e.g. C3, 4, and 5, APOB, VDB
Page 281 and 282:
1293 TRANSFORMING GROWTH FACTOR BET
Page 283 and 284:
mation was decreased to the same le
Page 285 and 286:
1312 EVALUATION OF THE SENSITIVITY
Page 287 and 288:
luted OFR and CRL. Culture media ex
Page 289 and 290:
urinary TCPy levels, blood and brai
Page 291 and 292:
activity. The dose-response curves
Page 293 and 294:
mice, each with 4 dose groups. One
Page 295 and 296:
exposure to both ATR and DACT has a
Page 297 and 298:
third tetratricopeptide repeats (TP
Page 299 and 300:
7d. 28d after TMT injury there was
Page 301 and 302:
subunits. Each cell type was treate
Page 303 and 304:
1394 COMPARATIVE EFFECTS OF METHYLM
Page 305 and 306:
1403 GENOTOXICITY AND PRE-NEOPLASTI
Page 307 and 308:
vated only in high-dose-treated ani
Page 309 and 310:
1421 DOSE-RESPONSE OF NAPHTHALENE-I
Page 311 and 312:
cisplatin; 1.2-, 1.9- and 2.9-fold
Page 313 and 314:
Day 11 and started to recover on Da
Page 315 and 316:
1448 DEVELOPMENT OF A METHOD FOR QU
Page 317 and 318:
1457 GLOBAL GENE PROFILING REVEALS
Page 319 and 320:
cluding mouse and human macrophage,
Page 321 and 322:
model of lung inflammation and host
Page 323 and 324:
1484 NANOTOXICOLOGY AND NANOHEALTH
Page 325 and 326:
throughput in vitro approach was us
Page 327 and 328:
1502 IMMUNOLOGICAL ASPECTS OF AN AN
Page 329 and 330:
(CIA) and the Streptococcal cell wa
Page 331 and 332:
sitizers were 100% concordant among
Page 333 and 334:
1530 MINIMAL RISK LEVELS FOR STYREN
Page 335 and 336:
ical groups in the field of regulat
Page 337 and 338:
vitro with this potentially insect-
Page 339 and 340:
their performance on toxicological
Page 341 and 342:
need for a better understanding of
Page 343 and 344: 1577 AN IN VITRO MODEL SYSTEM FOR A
Page 345 and 346: gene expression post-transcriptiona
Page 347 and 348: 1595 GENE EXPRESSION PROFILE OF RAT
Page 349 and 350: to confirm a hepatotoxic property o
Page 351 and 352: 1613 AN INVESTIGATION OF THE CLEARA
Page 353 and 354: its nuclear translocation was reduc
Page 355 and 356: were collected from TK animals at d
Page 357 and 358: egulated targets were selected for
Page 359 and 360: U/L after tetracycline. Minocycline
Page 361 and 362: peri-pubertal FasL-/- mice show a d
Page 363 and 364: showed similar levels of apoptosis
Page 365 and 366: 1676 TWO BIOMARKERS FOR EVALUATION
Page 367 and 368: motifs selected. This system was ap
Page 369 and 370: 1693 VOC SERUM LEVELS IN THE GENERA
Page 371 and 372: 1702 DOES THE CLOCK MAKE THE POISON
Page 373 and 374: those with high nickel content are
Page 375 and 376: isk assessment. However, unique cha
Page 377 and 378: model of APAP metabolism and glutat
Page 379 and 380: logically & morphologically similar
Page 381 and 382: posure, blood chemistry was analyze
Page 383 and 384: elated to oxidative stress by measu
Page 385 and 386: ostasis), but work is needed to tra
Page 387 and 388: tokine products during carcinogenes
Page 389 and 390: ways as chemical stressors and, the
Page 391 and 392: toxicity of nanomaterials relates s
Page 393: 1815 MEASURING COMPOUND SELECTIVITY
Page 397 and 398: cyanoacetic acid increased 2-3 fold
Page 399 and 400: 1845 IS THE PROMISCUITY OF THE ARYL
Page 401 and 402: crorarray analysis. RT-PCR results
Page 403 and 404: are a family of phase-II biotransfo
Page 405 and 406: ous labs. As a result of positive s
Page 407 and 408: down the doses may produce more tox
Page 409 and 410: spectively. Below 100 mg/l of gemfi
Page 411 and 412: 1900 GENERATION OF PRECISION CUT LI
Page 413 and 414: iomarkers or observation of lesions
Page 415 and 416: creased reticulocytes and lymphocyt
Page 417 and 418: statistically significant interacti
Page 419 and 420: monize sample preparation and analy
Page 421 and 422: NPC and sinonasal cancer in neighbo
Page 423 and 424: showed incidences of lung and nasal
Page 425 and 426: utylbenzenes, exhibited most simila
Page 427 and 428: 1975 DIFFERENTIAL MODULATION OF CYP
Page 429 and 430: organic As to MMA(V) and a lower ca
Page 431 and 432: ole in invasion and metastasis of c
Page 433 and 434: 3T3-L1 cells to low-levels of arsen
Page 435 and 436: 2011 IDENTIFICATION OF A NOVEL VX M
Page 437 and 438: This work was supported by Cooperat
Page 439 and 440: 2029 EFFICACY OF ENDOTRACHEAL ADMIN
Page 441 and 442: Diazepam injections and its combina
Page 443 and 444: 2047 ESTERASE ACTIVITIES AND HEMOST
Page 445 and 446:
nanoparticle-induced toxicity progr
Page 447 and 448:
house, were iv infused into rats ov
Page 449 and 450:
een explored. This study investigat
Page 451 and 452:
croscopic analysis revealed that on
Page 453 and 454:
egg yolk collected from turtles inh
Page 455 and 456:
consistency of results in both expe
Page 457 and 458:
2111 CYTOCHROME P450 3A5 GENOTYPE I
Page 459 and 460:
esidues of organophosphates or thei
Page 461 and 462:
manganism. Recent work from our lab
Page 463 and 464:
Aβ1-40 in CSF and hippocampus in P
Page 465 and 466:
2147 CATALASE MANIPULATIONS MODIFY
Page 467 and 468:
ation based on real-world exposure
Page 469 and 470:
NPs. Aggregation of citrate-stabili
Page 471 and 472:
2175 THE ROLE OF SURFACE CHEMISTRY
Page 473 and 474:
seen rapid uptake in biological ima
Page 475 and 476:
effect on uterine weight or vaginal
Page 477 and 478:
dicating widespread exposure. While
Page 479 and 480:
components into the liver parenchym
Page 481 and 482:
2223 ISOLATION AND DETECTION OF RIC
Page 483 and 484:
stored (-20 celsius degree). The co
Page 485 and 486:
2241 DDA, A BIOMARKER FOR ENVIRONME
Page 487 and 488:
2249 INTERACTION BETWEEN DIETARY SE
Page 489 and 490:
2258 PHARMACOKINETICS, EXCRETION BA
Page 491 and 492:
2267 SENSITIVE AND SPECIFIC FLUORES
Page 493 and 494:
2276 METABOLISM AND DISPOSITION OF
Page 495 and 496:
ment of hypertension in companion a
Page 497 and 498:
for the propyl series can be used f
Page 499 and 500:
2304 IN VITRO EXPOSURE AND EVALUATI
Page 501 and 502:
2313 THE SYNERGISTIC EFFECT OF SODI
Page 503 and 504:
genes that play a crucial role in M
Page 505 and 506:
2330 THE ROLE OF TRANSFORMING GROWT
Page 507 and 508:
ined following up to 96 h continuou
Page 509 and 510:
effect doses obtained with the rat
Page 511 and 512:
diated transcriptional response of
Page 513 and 514:
docrine disruptor activities of EDC
Page 515 and 516:
individuals. Week 6 results were qu
Page 517 and 518:
functionality of photosystem II and
Page 519 and 520:
wild mice (Mus musculus) from areas
Page 521 and 522:
2406 TOXICITY AND BIOACCUMULATION O
Page 523 and 524:
Isocitric acid is the acid in the h
Page 525 and 526:
2425 EFFECTS OF FUMONISINS IN ETHAN
Page 527 and 528:
centration(μg/g) were: 5.1-95.3; 2
Page 529 and 530:
2445 AUTOPHAGY IN DEVELOPMENT: A LI
Page 531 and 532:
sures to inhaled Mn in dust. Nevert
Page 533 and 534:
2466 CRITICAL EVALUATION OF ANIMAL
Page 535 and 536:
elationships predict that resting r
Page 537 and 538:
2489 COMPARATIVE TOXICITY OF BIODIE
Page 539 and 540:
2497 TRANSCRIPTIONAL REGULATION OF
Page 541 and 542:
2506 TOXICOLOGICAL CONSIDERATIONS O
Page 543 and 544:
launched with the aim of developing
Page 545 and 546:
forms mRNA expression levels were a
Page 547 and 548:
2534 CUTANEOUS WOUND HEALING IN THE
Page 549 and 550:
wells (0, 1, 5, 10, 25, 50, 100, an
Page 551 and 552:
2553 AN ORGANOTYPIC MICROLIVER PLAT
Page 553 and 554:
serum-free media. At 24 hrs, the gr
Page 555 and 556:
2572 INCREASED ARSENIC BIOACCESSIBI
Page 557 and 558:
nology to develop improved methods.
Page 559 and 560:
tuna, swordfish, or mako shark (3.5
Page 561 and 562:
nificantly reduce circulating thyro
Page 563 and 564:
grouped into 9 observation periods
Page 565 and 566:
histopathological or biochemical ev
Page 567 and 568:
exhibited a hyperactive phenotype,
Page 569 and 570:
the search of effective drugs for e
Page 571 and 572:
2644 COVALENT BINDING OF 14 C 2-MET
Page 573 and 574:
aries targeting all transcription f
Page 575 and 576:
(p 9 weeks) and CSC phenotype acqui
Page 577 and 578:
2673 IMMUNE-MEDIATED VASCULAR INJUR
Page 579 and 580:
for risk identification and charact
Page 581 and 582:
to control toxicant delivery in tob
Page 583 and 584:
Author Index (Continued) The numera
Page 585 and 586:
Page 587 and 588:
Page 589 and 590:
Page 591 and 592:
Page 593 and 594:
Page 595 and 596:
Page 597 and 598:
Page 599 and 600:
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Page 607 and 608:
Page 609 and 610:
Page 611 and 612:
Keyword Index (Continued) Arsenite
Page 613 and 614:
Keyword Index (Continued) Covalent
Page 615 and 616:
Keyword Index (Continued) flow cyto
Page 617 and 618:
Keyword Index (Continued) innate im
Page 619 and 620:
Keyword Index (Continued) nanoparti
Page 621 and 622:
Keyword Index (Continued) preservat
Page 623 and 624:
Keyword Index (Continued) Thrombocy
Page 625 and 626:
Toxicological Sciences The Official
show all

The Toxicologist - Society of Toxicology

Create successful ePaper yourself

Delete template?

Save as template?