Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity.

Expert Opinion on Drug Metabolism & Toxicology
Michelle C SangarNarayan G Avadhani

Abstract

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

References

Jan 1, 1991·Methods in Enzymology·R M ShayiqN G Avadhani
Jan 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·M SakaguchiT Omura
Jan 1, 1990·Free Radical Biology & Medicine·J G Liehr, D Roy
Jan 1, 1990·Pharmacology & Therapeutics·F J Gonzalez
Jan 1, 1988·Annual Review of Cell Biology·G Attardi, G Schatz
Jan 1, 1986·Annual Review of Biophysics and Biophysical Chemistry·D M EngelmanA Goldman
Oct 1, 1967·European Journal of Biochemistry·E R Simpson, G S Boyd
Oct 15, 1984·Journal of Molecular Biology·D EisenbergR Wall
Jun 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·M SakaguchiR Sato
Feb 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·S Bar-NunD D Sabatini
Sep 1, 1982·European Journal of Biochemistry·H Kuthan, V Ullrich
Jan 1, 1980·European Journal of Biochemistry·K M BothamG S Boyd
Jul 1, 1996·The Journal of Cell Biology·D T NgP Walter
Nov 15, 1996·Cell·H G WangJ C Reed
Apr 1, 1997·Physiological Reviews·C S Lieber
Apr 18, 1997·Forensic Science International : Synergy·K KudoT Nagata
Apr 29, 1998·JAMA : the Journal of the American Medical Association·J LazarouP N Corey
Oct 20, 1998·Chemical Research in Toxicology·J L BoltonS Qiu
Apr 20, 2000·The Journal of Clinical Investigation·I A LeclercqG R Robertson
Apr 27, 2000·The Journal of Biological Chemistry·E Szczesna-Skorupa, B Kemper
Jan 13, 2001·The Journal of Biological Chemistry·E P Neve, M Ingelman-Sundberg
Feb 15, 2001·Journal of Biomedical Science·M MaríA I Cederbaum
Feb 15, 2001·Journal of Biomedical Science·T ZimaP Popov
Feb 24, 2001·Genome Biology·D Werck-Reichhart, R Feyereisen

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Citations

Oct 12, 2012·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Liangbin XiaKe Wu
Apr 12, 2012·Antioxidants & Redox Signaling·Soo Han BaeSue Goo Rhee
Jan 21, 2012·The Veterinary Quarterly·J H Han van der Kolk
May 15, 2015·Chemical Research in Toxicology·Javier del PinoMaría Teresa Frejo
Sep 17, 2016·Omics : a Journal of Integrative Biology·Shareefa DalvieDan J Stein
May 23, 2019·The Journal of Biological Chemistry·Mrittika ChattopadhyayNarayan G Avadhani
Nov 4, 2017·Oxidative Medicine and Cellular Longevity·Suresh Kumar AnandasadagopanNarayan G Avadhani
Oct 31, 2018·International Journal of Molecular Sciences·Jesus Fernandez-AbascalMassimo Valoti
Dec 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Cailing LiuUla V Jurkunas
Dec 18, 2020·Frontiers in Endocrinology·Ali A HajeyahValerie B O'Donnell

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