A Practical Approach, Second Edition=Ronald D. Ho.pdf

548 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONkidney, and liver. 156 Partially purified LO from the cytosol of HICT at 8 to 10 weeks of gestation. 104,107oxidized model compounds, 104 and epoxidized ATB 1 in the presence of linoleic acid. 1076. Epoxide HydraseA study on prenatal changes in microsomal epoxide hydrase activity toward styrene oxide revealedthat the enzyme specific activity in rabbit fetal liver at GD 20 is less than 30% of the adult value. 75The activity was low in intestine, lung, and kidney on GD 28. In guinea pigs, fetal hepatic andintestinal epoxide hydrase activities were less than 10% of adult values, and levels of the enzymein lung and kidney were too low to measure. Phenobarbital caused dose-dependent induction (1.2to 3.1-fold) in human fetal hepatocytes obtained at 17 to 20 weeks’ gestation. 1597. Glutathione TransferaseHepatic GST titer is virtually undetectable in rodent embryos and early fetal liver, low near term,and reaches adult levels within a few weeks postpartum. 75,78,80,149,160 It appears that fetal GST activityis not induced when pregnant rats are treated with either DCNB or p,p-DDT. 149,160 On the otherhand, daily exposure of pregnant rats to styrene was found to be associated with a significant declinein GST activity in the fetal liver on GD 20. 151GST is abundant in human fetal liver. However, controversy surrounds the presence of acidic,basic, and neutral forms. 161–163 Mitra et al. 164 purified five GST isozymes from fetal liver (16 to 18weeks’ gestation) cytosol by affinity and ion-exchange HPLC. Two anionic forms with pI valuesof 5.5 (P-2) and 4.5 (P-3) and one basic form with the pI value of 8.7 (P-6) were clearly separated,and small amounts of two near neutral forms (P-4 and P-5) were also identified. Earlier, Radulovicet al. 165 studied the metabolism of methyl parathion by GST purified from human fetal livers at 14to 23 weeks of gestation. Methyl parathion was detoxified by O-dealkylation. HPLC, TLC, andradiometry indicated desmethyl parathion as the sole metabolite. Kulkarni et al. 166 reported theGSH conjugation of DBE by human fetal liver GST. Subsequently, 164 a novel model was devisedto assess the likelihood of developmental toxicity of DBE in humans. In the proposed in vitromodel, rat embryos (lacking GST) served as passive targets, and DBE bioactivation was mediatedby purified isozymes of human fetal liver GST. All of the tested human fetal liver GST isozymeswere found capable of bioactivating DBE. Covalent binding of radioactivity from DBE to DNAand protein suggested DBE bioactivation by GST, which was 144% and 212% higher, respectively,with the P-3 anionic form compared with the P-6 basic isoform. DBE bioactivation by the GST P-3 isoform resulted in developmental toxicity to cultured rat embryos. The results of this studysuggest that DBE may be a human developmental toxicant.8. UDP-Glucuronosyl TransferaseGlucuronide formation in the liver does not occur until after birth in guinea pigs, mice, and humans, 167,168and is barely measurable with o-aminophenol in rat fetuses near term. 160 In rats treated with TCDD onGD 5, fetal liver UGT activity toward p-nitrophenol and testosterone was first evident at GD 18 and22, respectively. 62 This activity increased rapidly, and a 20-fold increase in activity was observed byGD 22. In humans, UGT activity is measurable toward morphine, eostriol, and 2-naphthol in fetal livermicrosomes. 169 UGT activity in human fetal liver was low, about 0.1% of adult values with bilirubin, 170less than 5% with harmol, 171 and approximately 10% with 2-naphthol and morphine.9. SulfotransferaseCappiello et al. 172 conducted a comparative study of human SULT activity in the cytosolic fractionsof adult and fetal liver and placenta, using 2-naphthol as a substrate. Activity in fetal liver was© 2006 by Taylor & Francis Group, LLC