JULY/AUGUST 1991 VOLUME 4,NUMBER 4 @Copyright 1991 by the American Chemical Society
Invited Review Oxidation of Toxic and Carcinogenic Chemicals by Human Cytochrome P-450 Enzymes F. Peter Guengerich* Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146
Tsutomu Shimada Osaka Prefectural Institute of Public Health, Nakamichi, Higashinari-ku, Osaka 537,Japan Received January 25, 1991
The majority of toxic and carcinogenic chemicals do not produce their detrimental biological effects by themselves, except perhaps in acute doses. In most cases activation to electrophilic forms is necessary to produce molecules capable of reacting irreversibly with tissue nucleophiles. The pioneering work of the Millers demonstrated the need for such bioactivation in the formation of adducts involving proteins and nucleic acids (1-4). Such activation of chemicals is now known to be catalyzed by almost all of the enzymes involved in the biotransformation of xenobiotic chemicals (those not normally found in the body). Under the appropriate conditions, the so-called "phase 11" enzymes epoxide hydrolase (5,6), glutathione S-transferase (7,8), UDP-glucuronosyltransferase(9,lo),cysteine conjugate @-lyase(8,11,12), y-glutamyl transpeptidase (8), methylases (131,and others (14) may be involved in bioactivation as well as detoxication reactions. The majority of bioactivation reactions probably involve oxidation, and some of these detrimental oxidations are catalyzed by alcohol dehydrogenases (15),monoamine oxidase (16 ) , microsomal flavin-containing monooxygenase (17), and peroxidases such as prostaglandin synthase (18,19)and myeloperoxidase (20). However, the majority of oxidative bioactivation reactions can probably be attributed to P450.' There are several known models of activation of chemicals to electrophiles catalyzed by P-450s. Seven of these are shown in Scheme I and account for the bulk of possibilities, and these have been reviewed in more detail Abbrevintione: P-460,cytochrome P-4M);GSH, glutathione;"rp P-1, 3-amin~l,4-dimethyl-S~-p~do[4,3-~]indole.
Scheme I. Some Modes of Activation of Procarcinogens and -toxicants by P-450Enzymes P-450 1. RRNH -RR"OH 2.
7.
- RR"0R"
[RR'NT
x..i.,>H
