PRINCIPLES OF TOXICOLOGY - Biology East Borneo

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62 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION3.1 SITES <strong>OF</strong> BIOTRANSFORMATIONXenobiotic metabolism occurs in all organs and tissues in the body. Because many of the chemicalsmetabolized can have deleterious effects on the body, xenobiotic metabolism can be considered adefense mechanism that hastens the elimination of a toxic chemical and thus terminates the exposure.When viewed as a defense mechanism, it is not surprising that the exposure is best terminated at thepoint of exposure. These are the so-called portals of entry (shown as sites of absorption [a] forxenobiotics [X] in Figure 3.1), and constitute mainly the skin, lung, and intestinal mucosa. While drugmetabolizing enzymes are present in all these tissues (Table 3.2), and at relatively high activity in some,particularly intestine and lung, the liver is by far the most important tissue for xenobiotic metabolism(site [m] in Figure 3.1).Although it is not the first tissue of the body to be exposed to chemicals, the liver receives the entirechemical load absorbed from the gastrointestinal tract, which is the predominant portal of entry formost xenobiotics (Figure 3.1). The xenobiotic metabolizing enzymes are present in high concentrationsand the organ itself has large bulk, approximately 5 percent of the total body weight. Xenobioticsabsorbed from the lungs and skin can also quickly move to the liver for metabolism. Once in the liver,the highly vascular nature of the tissue and the intimate contact between blood and hepatocytes, whichcontain the xenobiotic metabolizing enzymes, allows for the rapid diffusion of chemicals in andmetabolites out (Figure 3.5).Although not a portal of entry, the kidney is an organ where xenobiotics are likely to beconcentrated during the excretion process, and this may be the reason for the relatively high levelof xenobiotic metabolizing enzymes in this tissue. Although the data presented in Table 3.2 arefrom laboratory animals, there is little evidence to contraindicate the existence of a similardistribution pattern in humans.Within the liver, hepatocytes or parenchymal cells are the major site of drug biotransformation,and within these cells it is the endoplasmic reticulum, which occupies about 15 percent of thehepatocyte volume and contains 20 percent of the hepatocyte protein, which houses the bulk ofthe critical drug metabolizing enzyme activity. (The nonparenchymal cells, including endothelialand Kupffer cells, constitute 35 percent of liver cell number but only contribute 5–10 percent ofliver mass. Their drug metabolizing enzyme activities are typically less than 20 percent of that inhepatocytes).When liver is carefully homogenized, fragments of the endoplasmic reticulum are converted tomicrosomes (an artifact of cell disruption). The drug-metabolizing enzymes located in the endoplasmicreticulum are often referred to as microsomal enzymes, and it is often stated that chemicals aremetabolized by liver microsomes. Enriched microsomal fractions are usually obtained by differentialsedimentation, either as a suspension with cytoplasm (10,000g supernatant) or as a sediment free ofcytosol (105,000g precipitate) (Table 3.3).Many important xenobiotic metabolizing enzymes reside in the cytoplasm and microsomal fractions(Figures 3.3 and 3.6).Oxidations and glucuronidations are the most common reactions occurring in microsomes. Theterminal oxidase responsible for many of the oxidations, cytochrome P450, represents about 5 percentof the microsomal protein under normal conditions; more if induction has occurred (see text below).Other flavoproteins necessary for cytochrome P450 function and epoxide hydrolase, an enzymeimportant in the further metabolism of epoxides formed by cytochrome P450–dependent oxidation,are also conveniently located in the endoplasmic reticulum (Figure 3.6). Microsomal metabolism intissues other than liver is seldom quantitatively important in overall drug elimination, but localgeneration of active metabolites may be important in drug-induced tissue damage, carcinogenesis, andother effects. Enzymes located in the cytoplasm of the hepatocyte catalyze a wide variety of both phaseI and phase II reactions. Dehydrogenases and esterases are examples of phase I enzymes foundpredominantly in the cytosol. The sulfotransferase and glutathione transferase enzymes also depictedin Figure 3.6 serve as examples of phase II enzymes that are similarly located.
3.1 SITES <strong>OF</strong> BIOTRANSFORMATION 63Figure 3.5 Diagrammatic rendition of hepatic lobule blood flow.TABLE 3.2 Drug-Metabolizing Enzyme Activities a in Various OrgansLungIntestineMucosaLiverKidneyCortexBrainRabbitCytochrome P450 0.4 0.34 1.45 0.33 0.02UDP-glucuronosyltransferase (p-nitrophenol) b 0.4 — 6.6 2.9Glutathione S-transferase (DCNB) b 5.3 — 21.9 7.4RatCytochrome P450 0.09 0.05 0.84 0.12 0.01Ethoxyresorufin demethylase (P4501A) 0.003 0.001 0.034 0.001Erythromycin demethylase (P4503A) — 0.12 0.47 0.06UDP-glucuronosyltransferase (p-nitrophenol) b 0.8 — 4.4 3.3Glutathione S-transferase (DCNB) b 2.1 — 76.4 3.8a All activities are expressed on a per milligram of protein basis (DCNB = 1,2-dichloro 4-nitrobenzene).b Litterst CL, Mimnaugh EG, Reagan RL, Gram TE, Drug Metab. Disp. 3: 259 (1975).
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CONTRIBUTORSLOUIS ADAMS, PH.D. Prof
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CONTENTSPREFACExvACKNOWLEDGMENTSxvi
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CONTENTSix7.3 Agents that Act on th
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CONTENTSxi15.4 Herbicides 35615.5 F
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CONTENTSxiii21.6 Population Issues
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xviPREFACE• The approach is scien
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PRINCIPLES OF TOXICOLOGY
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1 General Principles of ToxicologyG
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1.2 WHAT TOXICOLOGISTS STUDY 5Delay
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1.3 THE IMPORTANCE OF DOSE AND THE
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1.3 THE IMPORTANCE OF DOSE AND THE
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Page 41 and 42: 26 GENERAL PRINCIPLES OF TOXICOLOGY
Page 51 and 52: 36 ABSORPTION, DISTRIBUTION, AND EL
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Page 68 and 69: 2.5 SUMMARY 53the transfer from liv
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Page 72 and 73: 58 BIOTRANSFORMATION: A BALANCE BET
Page 74 and 75: 60Figure 3.3 Xenobiotic metabolism
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Page 102 and 103: 88 HEMATOTOXICITY: CHEMICALLY INDUC
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.2 TYPES OF LIVER INJURY 117cause
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5.2 TYPES OF LIVER INJURY 119Exampl
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5.2 TYPES OF LIVER INJURY 121TABLE
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5.2 TYPES OF LIVER INJURY 123to pro
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5.3 EVALUATION OF LIVER INJURY 125f
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REFERENCES AND SUGGESTED READING 12
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6 Nephrotoxicity: Toxic Responses o
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.2 FUNCTIONAL MEASUREMENTS TO EVAL
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6.3 ADVERSE EFFECTS OF CHEMICALS ON
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146 NEUROTOXICITY: TOXIC RESPONSES
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8 Dermal and Ocular Toxicology: Tox
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8.2 FUNCTIONS 159corneum is the pri
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8.3 CONTACT DERMATITIS 161TABLE 8.2
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8.3 CONTACT DERMATITIS 163mucous me
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8.3 CONTACT DERMATITIS 165light to
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8.4 SUMMARY 167The structure of the
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9 Pulmonotoxicity: Toxic Effects in
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9.1 LUNG ANATOMY AND PHYSIOLOGY 171
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.3 SUMMARY 185Industrially Related
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190 IMMUNOTOXICITY: TOXIC EFFECTS O
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11 Reproductive ToxicologyREPRODUCT
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11.1 MALE REPRODUCTIVE TOXICOLOGY 2
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11.2 FEMALE REPRODUCTIVE TOXICOLOGY
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11.3 DEVELOPMENTAL TOXICOLOGY 225de
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11.3 DEVELOPMENTAL TOXICOLOGY 227af
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11.3 DEVELOPMENTAL TOXICOLOGY 229ri
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11.3 DEVELOPMENTAL TOXICOLOGY 231to
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11.4 CURRENT RESEARCH CONCERNS 233T
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11.4 CURRENT RESEARCH CONCERNS 235
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12 Mutagenesis and Genetic Toxicolo
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12.2 GENETIC FUNDAMENTALS AND EVALU
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TABLE 12-1. Correspondence of the G
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12.3 NONMAMMALIAN MUTAGENICITY TEST
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.5 OCCUPATIONAL SIGNIFICANCE OF M
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REFERENCES CITED AND SUGGESTED READ
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13 Chemical CarcinogenesisCHEMICAL
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13.1 THE TERMINOLOGY OF CANCER 267H
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13.3 CARCINOGENESIS BY CHEMICALS 26
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Figure 13.1 Schematic diagram of th
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Figure 13.4 Metabolic activation of
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13.4 MOLECULAR ASPECTS OF CARCINOGE
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Figure 13.7 DNA damage leads to p53
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.6 INTERPRETATION ISSUES RAISED B
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13.7 EMPIRICAL MEASURES OF RELIABIL
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13.8 OCCUPATIONAL CARCINOGENS 301TA
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13.8 OCCUPATIONAL CARCINOGENS 303TA
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13.9 CANCER AND OUR ENVIRONMENT 305
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13.10 CANCER TRENDS AND THEIR IMPAC
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13.11 SUMMARY 321from non-Hodgkin
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14 Properties and Effects of Metals
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14.2 SPECIATION OF METALS 327Most o
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14.3 PHARMACOKINETICS OF METALS 329
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14.4 TOXICITY OF METALS 331reflex i
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14.4 TOXICITY OF METALS 333Several
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14.5 SOURCES OF METAL EXPOSURE 335H
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14.6 TOXICOLOGY OF SELECTED METALS
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14.7 SUMMARY 343Zinc is required fo
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15 Properties and Effects of Pestic
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15.1 ORGANOPHOSPHATE AND CARBAMATE
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.4 HERBICIDES 357ClClO CH 2 C OOH
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15.5 FUNGICIDES 359temperatures as
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15.7 FUMIGANTS 361thallium sulfate-
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16 Properties and Effects of Organi
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TABLE 16.1 Physicochemical Properti
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16.2 BASIC PRINCIPLES 371TABLE 16.2
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16.2 BASIC PRINCIPLES 373Once absor
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16.2 BASIC PRINCIPLES 375the additi
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16.3 TOXIC PROPERTIES OF REPRESENTA
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16.10 TOXIC PROPERTIES OF REPRESENT
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16.15 TOXIC PROPERTIES 403observed
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16.18 SULFUR-SUBSTITUTED SOLVENTS 4
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17 Properties and Effects of Natura
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17.3 NATURAL ROLES OF TOXINS AND VE
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17.4 MAJOR SITES AND MECHANISMS OF
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17.5 TOXINS IN UNICELLULAR ORGANISM
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17.6 TOXINS OF HIGHER PLANTS 417phy
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17.6 TOXINS OF HIGHER PLANTS 419whi
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17.6 TOXINS OF HIGHER PLANTS 421TAB
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17.7 ANIMAL VENOMS AND TOXINS 423of
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17.7 ANIMAL VENOMS AND TOXINS 425ac
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17.7 ANIMAL VENOMS AND TOXINS 427co
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17.7 ANIMAL VENOMS AND TOXINS 429Fi
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17.8 TOXIN AND VENOM THERAPY 431One
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18 Risk AssessmentRISK ASSESSMENTRO
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18.1 RISK ASSESSMENT BASICS 439Step
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18.1 RISK ASSESSMENT BASICS 441For
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18.2 HAZARD IDENTIFICATION 443chemi
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.4 DOSE-RESPONSE ASSESSMENT 449Af
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18.4 DOSE-RESPONSE ASSESSMENT 451me
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18.4 DOSE-RESPONSE ASSESSMENT 453Fi
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18.4 DOSE-RESPONSE ASSESSMENT 455No
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18.4 DOSE-RESPONSE ASSESSMENT 457Fi
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18.4 DOSE-RESPONSE ASSESSMENT 459Ge
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18.5 RISK CHARACTERIZATION 461likel
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18.6 PROBABILISTIC VERSUS DETERMINI
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18.7 EVALUATING RISK FROM CHEMICAL
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18.7 EVALUATING RISK FROM CHEMICAL
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18.8 COMPARATIVE RISK ANALYSIS 469r
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18.8 COMPARATIVE RISK ANALYSIS 471T
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18.9 RISK COMMUNICATION 473TABLE 18
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480 EXAMPLE OF RISK ASSESSMENT APPL
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500 OCCUPATIONAL AND ENVIRONMENTAL
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21 Epidemiologic Issues inOccupatio
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21.3 TYPES OF EPIDEMIOLOGIC STUDIES
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21.5 DISEASE AND HUMAN HEALTH EFFEC
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21.8 MEASUREMENT OF ASSOCIATION OR
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21.9 BIAS 519increased or decreased
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524 CONTROLLING OCCUPATIONAL AND EN
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556 GLOSSARYaliphatic Organic compo
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558 GLOSSARYbenign tumor A new tiss
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560 GLOSSARYcytokinesis The divisio
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562 GLOSSARYerythropoietic stimulat
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564 GLOSSARYinhalation route The mo
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566 GLOSSARYmitochondria Small sphe
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568 GLOSSARYoral route The entry of
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570 GLOSSARYporphyrin Any of a grou
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572 GLOSSARYspirometry The measurem
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INDEXAbsorbed dose, defined, 4Absor
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INDEX 577Area under the tissue conc
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INDEX 579animal studies, 297cellula
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INDEX 581speciation of, 327-328Corp
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INDEX 583organ-specific activities,
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INDEX 585Follicle-stimulating hormo
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INDEX 587fatty liver, 120-122hepato
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INDEX 589Isoniazid metabolism, path
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INDEX 591Mechanistic toxicology, as
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INDEX 593Nephropathy:defined 130nep
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INDEX 595neurobehavioral sequelae,
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INDEX 597Probability density functi
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INDEX 599Rodenticides, 360.-361sodi
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INDEX 601Safe Human Dose (SHD) appr
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INDEX 603drug metabolism factors, 7
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