MECHANISMS OF CYTOCHROME-P450 AND PEROXIDASE-CATALYZED XENOBIOTIC METABOLISM

被引:82
作者
HOLLENBERG, PF
机构
[1] Department of Pharmacology, Wayne St. Univ. School of Med., Detroit, MI 48201
关键词
CYTOCHROME-P450; PEROXIDASE; MONOOXYGENASE; MIXED-FUNCTION OXIDASE; HYDROXYLATION;
D O I
10.1096/fasebj.6.2.1537457
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cytochrome P450 enzyme systems catalyze the metabolism of a wide variety of naturally occurring and foreign compounds by reactions requiring NADPH and O2. Cytochrome P450 also catalyzes peroxide-dependent hydroxylation of substrates in the absence of NADPH and O2. Peroxidases such as chloroperoxidase and horseradish peroxidase catalyze peroxide-dependent reactions similar to those catalyzed by cytochrome P450. The kinetic and chemical mechanisms of the NADPH and O2-supported dealkylation reactions catalyzed by P450 have been investigated and compared with those catalyzed by P450 and peroxidases when the reactions are supported by peroxides. Detailed kinetic studies demonstrated that chloroperoxidase- and horseradish peroxidase-catalyzed N-demethylations proceed by a Ping Pong Bi Bi mechanism whereas P450-catalyzed O-dealkylations proceed by sequential mechanisms. Intramolecular isotope effect studies demonstrated that N-demethylations catalyzed by P450s and peroxidases proceed by different mechanisms. Most hemeproteins investigated catalyzed these reactions via abstraction of an alpha-carbon hydrogen whereas reactions catalyzed by P-450 and chloroperoxidase proceeded via an initial one-electron oxidation followed by alpha-carbon deprotonation. O-18-Labeling studies of the metabolism of NMC also demonstrated differences between the peroxidases and P450s. Because the hemeprotein prosthetic groups of P450, chloroperoxidase, and horseradish peroxidase are identical, the differences in the catalytic mechanisms result from differences in the environments provided by the proteins for the heme active site. It is suggested that the axial heme-iron thiolate moiety in P450 and chloroperoxidase may play a critical role in determining the mechanism of N-demethylation reactions catalyzed by these proteins.
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页码:686 / 694
页数:9
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