PRINCIPLES OF TOXICOLOGY

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66 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION Cytochrome P450 is a collective term for a group of related hemoproteins, all with a molecular weight (MW) around 50,000 daltons, which as will be seen later, differ in their substrate selectivity and in their ability to be induced and inhibited by drugs and chemicals (Table 3.4). Cytochrome P450–catalyzed oxidations are categorized by the nature of the atom that is oxidized (see Figure 3.8). Subsequent to the oxidation, the oxygen atom from molecular oxygen may be retained within the major fragment of the chemical or it may be eliminated by molecular rearrangement (e.g., O and N dealkylations). Whatever the atom oxidized, or the name given to the reaction, the cytochrome P450–mediated oxidation involves the same cyclic three-step series (Figure 3.9). Step 1. The xenobiotic [X] first binds to the cytochrome at a substrate binding site on the protein and alters the conformation sufficiently to enable the efficient transfer of electrons to the heme from NADPH via a nearby (see Figure 3.6) flavoprotein, NADPH cytochrome P450 reductase. (The activity of this FAD- and FMN-containing flavoprotein is often determined experimentally using exogenously added mitochondrial cytochrome c rather than microsomal cytochrome P450 as the electron acceptor and so is often identified as NADPH cytochrome c reductase). The conformational change can sometimes be seen in vitro (in the absence of electron transfer) as an alteration of the heme from a low-spin to a high-spin state, which results in a blue shift in the absorbance maximum of the hemoprotein. The gain at 390 nm and loss at 420 nm, when seen by difference spectroscopy, is termed a type I binding spectrum (not to be confused with phase I metabolism). Step 2. The reduction of the heme iron from its normal ferric state to the ferrous state allows a molecule of oxygen (O–O) to bind (the binding of CO rather than oxygen to ferrous cytochrome P450 in the in vitro situation provides a characteristic absorbance maximum around 450 nm, which gives this cytochrome its name). Step 3. The ternary complex of xenobiotic, cytochrome, and oxygen receives another electron, either through the same flavoprotein as before or through an alternative path involving a different flavoprotein in which the electron is first passed through cytochrome b5, another cytochrome present in the endoplasmic reticulum (see Figure 3.6). This alternate pathway for the second electron can also use NADH as the pyridine nucleotide electron donor. The addition of the second electron to the ternary complex results in a eventual splitting of the molecular oxygen, one atom of which oxidizes the chemical, the other atom picking up protons to form water, returning ferric cytochrome P450 to repeat the cycle. Flavoprotein-catalyzed oxidations differ from cytochrome P450–catalyzed oxidations in mechanism and in substrate selectivity. For the flavoproteins (a 65,000-dalton protein containing only FAD), the enzyme forms an activated oxygen complex (“cocked gun”) and the addition of a metabolizable chemical discharges this, in the process of becoming oxidized. The electrophilic oxygenated species attacks nucleophilic centers. A wide range of chemicals can thus be metabolized by this flavoprotein; the important feature for metabolism being a heteroatom (nitrogen, sulfur) presenting a lone pair of electrons (Table 3.5). Some compounds are metabolized both by flavin-containing monooxygenases and cytochrome P450 but to different products. An example is dimethylaniline, which is metabolized to the N-oxide by the flavoprotein and is N-demethylated by cytochrome P450. Nonmicrosomal Oxidations in other subcellular organelles can be catalyzed by flavoproteins (e.g., monoamine oxidase in mitochondria) or pyridine nucleotide linked dehydrogenases (e.g., alcohol and aldehyde dehydrogenases in cytoplasm). Dehydrogenase-catalyzed oxidations do not involve molecular oxygen. The oxidation of the chemicals or drugs occurs through electron transfer to a pyridine nucleotide, usually NAD + . Most of the dehydrogenases are cytoplasmic in location. The most noteworthy of this class of enzymes in humans is the dehydrogenase responsible for the metabolism of ethanol. In contrast to the major
TABLE 3.4 Important Cytochrome P450s a Forms Present in Substrates/ Subfamily Rat Rabbit Human Mouse Tissue Reactions Inducers Inhibitors 1A 1,2 1,2 1,2 1,2 liver, EH ethoxyresorufin, PCB, PAH, TCDD, 3MC, 7,8-benzoflavone, phenacetin deE, caffeine 3 isosafrole, omeprazole ellipticine, furafylline deM, benzopyrene, aflatoxin, cooked-food heterocyclic amines, NBI 2A 1,2 4,5 PAH (2A1) 2B 1,2 4 9,10,13 pentoxyresorufin, PB benzphetamine 2C 6,7 liver, GI PB 8,9,10 tolbutamide PB, RIF sulfaphenazole 11,12,13 sex, maturation, 17,18,19 S-mephenytoin 4-OH, tranylcypromine debrisoquine 4-OH, RIF quinidine 2D 6 9,10,11, liver, EH sparteine, 12,13 dextromethorphan, bufuralol 1′-OH 2E 1 1,2 1 1 liver, EH chlozoxazone, ethanol ethanol, disulfiram dimethylnitrosamine, ketones, pyridine, acetaminophen, CCl4, isoniazid 4-nitrophenol-OH 2F 1 2 lung 3-methylindole naphthalene 67
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PRINCIPLES OF TOXICOLOGY
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This book is printed on acid-free p
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vi CONTRI BUTORS PAUL J. MIDDENDORF
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viii CONTENTS 4 Hematotoxicity: Che
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x CONTENTS 12 Mutagenesis and Genet
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xii CONTENTS III APPLICATIONS 435 1
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PREFACE Purpose of This Book Princi
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ACKNOWLEDGMENTS A text of this unde
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PART I Conceptual Aspects Principle
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4 GENERAL PRINCIPLES OF TOXICOLOGY
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Page 51 and 52: 36 ABSORPTION, DISTRIBUTION, AND EL
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Page 73 and 74: BIOTRANSFORMATION: A BALANCE BETWEE
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Page 77 and 78: Figure 3.5 Diagrammatic rendition o
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Page 107 and 108: 4.3 THE MYELOID SERIES 93 to contra
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Page 125 and 126: 112 HEPATOTOXICITY: TOXIC EFFECTS O
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118 HEPATOTOXICITY: TOXIC EFFECTS O
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130 NEPHROTOXICITY: TOXIC RESPONSES
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7 Neurotoxicity: Toxic Responses of
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ions moving out of the cell brings
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an effect seen with some neurotoxic
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7.4 INTERACTIONS OF INDUSTRIAL CHEM
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• A study of the patient’s hist
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• Although much of the damage whi
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158 DERMAL AND OCULAR TOXICOLOGY Fi
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160 DERMAL AND OCULAR TOXICOLOGY P4
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162 DERMAL AND OCULAR TOXICOLOGY ca
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164 DERMAL AND OCULAR TOXICOLOGY ke
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166 DERMAL AND OCULAR TOXICOLOGY Fi
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168 DERMAL AND OCULAR TOXICOLOGY
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170 PULMONOTOXICITY: TOXIC EFFECTS
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10 Immunotoxicity: Toxic Effects on
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10.2 BIOLOGY OF THE IMMUNE RESPONSE
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10.2 BIOLOGY OF THE IMMUNE RESPONSE
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certain situations immunosuppressio
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10.5 TESTS FOR DETECTING IMMUNOTOXI
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10.6 SPECIFIC CHEMICALS THAT ADVERS
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10.6 SPECIFIC CHEMICALS THAT ADVERS
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animal origin have also been shown
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The mainstay of treatment of multip
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PART II Specific Areas of Concern P
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210 REPRODUCTIVE TOXICOLOGY continu
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212 REPRODUCTIVE TOXICOLOGY Underst
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214 REPRODUCTIVE TOXICOLOGY spermat
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216 REPRODUCTIVE TOXICOLOGY gonadot
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218 REPRODUCTIVE TOXICOLOGY TABLE 1
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Figure 11.3 Cycle of follicular dev
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222 REPRODUCTIVE TOXICOLOGY Figure
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224 REPRODUCTIVE TOXICOLOGY TABLE 1
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226 Figure 11.5 Developmental tree
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228 REPRODUCTIVE TOXICOLOGY is clea
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230 REPRODUCTIVE TOXICOLOGY genital
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232 REPRODUCTIVE TOXICOLOGY to occu
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234 REPRODUCTIVE TOXICOLOGY these r
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236 REPRODUCTIVE TOXICOLOGY Two imp
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238 REPRODUCTIVE TOXICOLOGY Sundara
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240 MUTAGENESIS AND GENETIC TOXICOL
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248 Figure 12.5 Example of DNA addu
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TABLE 12-3 NTP and Gene-Tox Evaluat
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266 CHEMICAL CARCINOGENESIS 13.1 TH
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268 CHEMICAL CARCINOGENESIS TABLE 1
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270 CHEMICAL CARCINOGENESIS researc
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272 CHEMICAL CARCINOGENESIS Figure
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276
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280 CHEMICAL CARCINOGENESIS 13.4 MO
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286 CHEMICAL CARCINOGENESIS make a
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288 Figure 13.8 A genetic model of
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290 CHEMICAL CARCINOGENESIS Increas
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292 CHEMICAL CARCINOGENESIS may be
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294 CHEMICAL CARCINOGENESIS • The
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296 CHEMICAL CARCINOGENESIS evaluat
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298 CHEMICAL CARCINOGENESIS In rats
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302 CHEMICAL CARCINOGENESIS with ex
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316 CHEMICAL CARCINOGENESIS similar
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324 CHEMICAL CARCINOGENESIS Knudson
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326 PROPERTIES AND EFFECTS OF METAL
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332 TABLE 14.2 Target Organ Toxicit
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346 PROPERTIES AND EFFECTS OF PESTI
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368 PROPERTIES AND EFFECTS OF ORGAN
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370 TABLE 16.1 (Continued) Water So
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410 PROPERTIES AND EFFECTS OF NATUR
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PART III Applications Principles of
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438 RISK ASSESSMENT 18.1 RISK ASSES
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440 RISK ASSESSMENT control populat
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442 RISK ASSESSMENT there are some
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444 RISK ASSESSMENT • It identifi
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446 RISK ASSESSMENT chemical poses
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448 RISK ASSESSMENT • Estimating
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450 RISK ASSESSMENT Figure 18.3 Est
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452 RISK ASSESSMENT • As discusse
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454 RISK ASSESSMENT divided by a de
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456 RISK ASSESSMENT Because low-dos
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458 RISK ASSESSMENT TABLE 18.1 Expe
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460 RISK ASSESSMENT leading to impo
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462 RISK ASSESSMENT characterizatio
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464 RISK ASSESSMENT Figure 18.7 Sim
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466 RISK ASSESSMENT The RPF values
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468 RISK ASSESSMENT producing the e
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470 RISK ASSESSMENT TABLE 18.4b Can
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472 RISK ASSESSMENT TABLE 18.7 Acti
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474 RISK ASSESSMENT A second reason
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476 RISK ASSESSMENT Barnard, R. C.,
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19 Example of Risk Assessment Appli
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19.3 LEAD EXPOSURE AND WOMEN OF CHI
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19.4 PETROLEUM HYDROCARBONS: ASSESS
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19.4 PETROLEUM HYDROCARBONS: ASSESS
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19.5 RISK ASSESSMENT FOR ARSENIC 48
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19.5 RISK ASSESSMENT FOR ARSENIC 48
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19.6 REEVALUATION OF THE CARCINOGEN
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REFERENCES AND SUGGESTED READING RE
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20 Occupational and Environmental H
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20.1 DEFINITION AND SCOPE OF THE PR
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20.4 HUMAN RESOURCES IMPORTANT TO O
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treatment, or medical removal from
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Academic practices welcome complica
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Occupational and environmental medi
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512 EPIDEMIOLOGIC ISSUES IN OCCUPAT
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22 Controlling Occupational and Env
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22.2 EXPOSURE LIMITS 525 The TLVs
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modified “reference doses” to r
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observation process, followed by re
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• Hazard-specific training to ens
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22.3 PROGRAM MANAGEMENT 533 Conside
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Figure 22.1 22.3 PROGRAM MANAGEMENT
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fundamental viability of the work p
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Figure 22.2. 22.3 PROGRAM MANAGEMEN
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• Physical assessment and fit tes
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The study was designed to minimize
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TABLE 22.3 Margins of Safety at For
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top, and numerous slots with smalle
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TABLE 22.5 Comparison of Time-Weigh
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• Housing or building code violat
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• Environmental exposure limits,
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GLOSSARY Glossary absorption The mo
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GLOSSARY 557 antipyretic An agent t
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GLOSSARY 559 chloracne An acne-like
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GLOSSARY 561 eczema A superficial i
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GLOSSARY 563 hemolytic anemia Anemi
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GLOSSARY 565 lipoprotein Any of a g
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GLOSSARY 567 necrosis Death of one
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pernicious anemia The progressive,
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GLOSSARY 571 cells have both endoth
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GLOSSARY 573 tolerance The ability
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576 INDEX Allergic reaction (contin
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578 INDEX Biotransformation (contin
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580 INDEX Children’s health statu
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582 INDEX Diet and nutrition (conti
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584 INDEX Estrogens: endocrine disr
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586 INDEX Hair, toxic agent excreti
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588 INDEX hnmunoglobulins: autoimmu
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590 INDEX Loop of Henle, structure
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592 INDEX Mixed exposure patterns,
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594 INDEX Nutritional deficiencies,
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596 INDEX Pesticides (continued) Pe
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598 INDEX Relative potency factor (
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600 INDEX Solvents (continued) phys
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602 INDEX Tumorigenesis (continued)
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