Page 174 - The Toxicology of Fishes

154 The Toxicology of Fishes

Amino Acid Conjugation .............................................................................................................205
Overview.............................................................................................................................205
Enzymes Specificity, Regulation, and Inhibition...............................................................206
Acetylation ...................................................................................................................................206
Overview.............................................................................................................................206
Enzyme Specificity, Regulation, and Inhibition.................................................................207
Toxicological Relevance ........................................................................................................................207
Benzo(a)pyrene ............................................................................................................................207
Aflatoxin B ..................................................................................................................................209
1
Organophosphate Esters and Carbamates....................................................................................213
Conclusions............................................................................................................................................215
References..............................................................................................................................................216

Introduction

Biotransformation is a two-phase process catalyzed primarily through enzymatic reactions that often
radically alter the chemistry of nonpolar lipophilic chemicals to polar water-soluble metabolites pre-
dominately leading to detoxification and elimination of the parent compounds. Unfortunately, the alter-
ation of chemistry required for enhanced polarity often creates reactive intermediates through
bioactivation, which can be more biologically hazardous than the initial parent compounds. The phase I
process either adds or exposes polar atoms within a xeno- or endobiotic compound. Three general phase I
reactions include oxidation, reduction, and hydrolysis (Table 4.1). When polarity has been enhanced
through phase I reactions, phase II reactions generally attempt to further enhance polarity through
conjugation of the phase I product with a bulky polar endogenous molecule. Alternatively, phase II
reactions may protect against bioactivation by masking functional groups (i.e., amines) prone to reactive
intermediate formation with groups that likely provide steric hindrance (i.e., methyl, acetyl) rather than
augmented polarity (Table 4.1).

Phase I Reactions

Oxidation
Various enzymes are involved in the oxidation of xeno- and endobiotic compounds. Dehydrogenases oxidize
substrates transferring electrons to an electron-deficient acceptor that is typically an essential cofactor for
+
catalysis (e.g., NAD ). Oxygenases catalyze the incorporation of molecular oxygen into molecules, and
water is the source of oxygen for oxidases. Peroxidases derive oxygen from peroxide cofactors.
Cytochrome P450 Family of Drug Metabolizing Enzymes
Overview
The most dominant enzyme system responsible for oxidation processes in phase I biotransformation is
the cytochrome P450 monooxygenases. The cytochrome P450s (CYPs) constitute a superfamily of heme-
containing proteins that catalyze biological oxidation and reduction reactions. Klingenberg (1958) and
Garfinkel (1958) first reported that hepatic microsomes contain a pigment that binds carbon monooxide
with an unusual visible absorption maximum at 450 nm in its CO-reduced difference spectrum. Omura
and Sato (1962) discovered that this pigment was a b-type cytochrome and called it cytochrome P450.
The hepatic microsomal CYP system has broad substrate specificity and is responsible for oxidative
metabolism of many structurally diverse endogenous and xenobiotic compounds. CYP enzymes are
important for converting lipophilic foreign chemicals into more water-soluble products for excretion
and, hence, detoxification. On the other hand, CYP enzymes catalyze the conversion of certain com-
pounds such as polycyclic aromatic hydrocarbons (PAHs) and nitrosamines into more toxic intermediates.
Constitutive CYP forms that appeared early in evolution are involved in biosynthesis (anabolism) of
endogenous substances such as steroids, fatty acids, vitamins, bile acids, leukotrienes, thromboxanes,