The Mechanism of Microsomal Azoreduction: Predictions Based on Electronic Aspects of Structure-Activity Relationships
Abstract
DRUG METABOLISM REVIEWS, 27(3), 497-5 16 (1995) THE MECHANISM OF MICROSOMAL AZOREDU CTlO N: PREDlCTlO NS BASED ON ELECTRONIC ASPECTS OF STRUCTURE-ACTIVITY RELATlONS HIPS* SHMUEL ZBAIDA Department of Drug Metabolism and Pharmacokinetics Schering-Plough Research Institute 2015 Galloping Hill Road Kenilworth, New Jersey 07033-0539 I. INTRODUCTION ........................................................ 111. A STEPWISE MECHANISM OF TWO ONE-ELECTRON REDUCTIONS ............................................................ 498 11. REQUIREMENTS FOR MICROSOMAL AZOREDUCTION .. 499 501 504 IV. I- AND S-SUBSTRATE DYES ....................................... V. CYCLIC VOLTAMMETRY: A TOOL FOR DISTINGUISHING I- AND S-SUBSTRATES FROM NONSUBSTRATE DYES .............................................. VI. VERIFICATION OF MICROSOMAL AZOREDUCTASE MECHANISM ............................................................ 505 506 'This paper was refereed by Leonard C. Keifer, Ph.D., Senior Scientist, HERD-7403, U.S. Environmental Protection Agency, Washington, DC 20460. 497 Copyright 0 1995 by Marcel Dekker. Inc. 498 ZBAIDA 508 510 51 1 VII. SENSITIVITY TO CARBON MONOXIDE ...................... VIII. SUMMARY ............................................................. References ................................................................ I. INTRODUCTION The four major biotransformation pathways are oxidation, hydrolysis, conjugation, and reduction. The reductive pathway has been the least investigated. An excellent review by Mc Lane et al. [l] on the predominant reductive reactions appeared in this journal. Recently, Levine [2] discussed the metabolism of azo dyes and its implication for both activation and detoxification. Azo dyes are metabolized