Molecular Mechanisms Regulating the Mitochondrial Targeting of Microsomal Cytochrome P450 EnzymesMolecular Mechanisms Regulating the Mitochondrial Targeting of Microsomal Cytochrome P450 Enzymes

Taeho      Ahn; Chul-Ho      Yun

doi:10.2174/138920010794479655

Abstract

Cytochrome P450 enzymes (CYPs) are a superfamily of monooxygenases found in almost all living organisms. CYPs are predominantly localized in the endoplasmic reticulum membranes as integral membrane proteins, where they metabolize a variety of endogenous and xenobiotic compounds. CYPs also reside in other subcellular compartments, including the plasma membranes and mitochondria. CYP localization in mitochondria is regulated in one of two ways: (1) direct targeting of inherent CYPs with canonical mitochondrial signals in their protein sequence after synthesis in the cytosol or (2) mitochondrial localization of microsomal CYPs after processing of the NH2-terminal region. Microsomal CYPs targeted to mitochondria demonstrate conventional or altered catalytic activities using electrons provided by the mitochondrial electron transport system. Mechanisms of microsomal CYP targeting to mitochondria, regulation of localization, and the implications of these in drug metabolism are described in the present review.

Keywords: cytochrome P450, drug metabolism, microsome, mitochondria, signal sequence, targeting, monooxygenases, endoplasmic reticulum membranes, electron transport system, dealkylation, ER membrane, B cell-associated protein 31, BAP31, Mitochondrial CYPs, NADPH, monooxygenation, human CYP11A1, mitochondrial CYP, adrenodoxin reductase, rat microsomal CYP1A1, Microsomal CYP2E1, mitochondrial, steroid hormone biosynthesis, pregnenolone, bile acid bio-syntheses, Adx, AdR, pro-tein kinase, Hsp70, Hsp90, anti-depressants, anti-convulsants, opiates, erythromycin, EET-EAs, mtCYP2E1, hydroxylation, N-demethylation, O-dealkylation, S-oxidation, deamination, epoxidation, xenobiotic