Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity.
BACKGROUND
Microsomal CYPs are critical for drug metabolism and toxicity. Recent studies show that these CYPs are also present in the mitochondrial compartment of human and rodent tissues. Mitochondrial CYP1A1 and 2E1 show both overlapping and distinct metabolic activities compared to microsomal forms. Mitochondrial CYP2E1 also induces oxidative stress. The mechanisms of mitochondria targeting of CYPs and their role in drug metabolism and toxicity are important factors to consider while determining the drug dose and in drug development.


METHODS
This review highlights the mechanisms of bimodal targeting of CYP1A1, 2B1, 2E1 and 2D6 to mitochondria and microsomes. The review also discusses differences in structure and function of mitochondrial CYPs.


RESULTS
A comprehensive review of the literature on drug metabolism in the mitochondrial compartment and their potential for inducing mitochondrial dysfunction.


CONCLUSIONS
Studies on the biochemistry, pharmacology and pharmacogenetic analysis of CYPs are mostly focused on the molecular forms associated with the microsomal membrane. However, the mitochondrial CYPs in some individuals can represent a substantial part of the tissue pool and contribute in a significant way to drug metabolism, clearance and toxicity.
Sangar
Michelle C
MC
University of Pennsylvania, School of Veterinary Medicine, Department of Animal Biology and the Mari Lowe Center for Comparative Oncology, Philadelphia, PA 19104, USA.
Bansal
Seema
S
Avadhani
Narayan G
NG
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D018384:Oxidative Stress; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012377:Rodentia
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System