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

Abstract

Importance of the field-Microsomal cytochrome P450s 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.Areas covered in this review-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.What the readers will gain-A comprehensive review of the literature on drug metabolism in the mitochondrial compartment, and their potential for inducing mitochondrial dysfunction.Take home message-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.

Human Cytochrome P450 2E1 Mutations That Alter Mitochondrial Targeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models

“…These observations lend further support to our hypothesis on bimodal protein targeting driven by the chimeric N-terminal signals and also provide evidence for a physiological significance of bimodal targeting and its role in diseases. Previously we showed, for family 1 and 2 CYPs, that either proteolytic processing or PKA/PKC-mediated phosphorylation at the N-terminal signal domain can activate the chimeric signals causing increased mitochondrial targeting of proteins (24,48,71,72,73). In this study, we conclude that an additional genetic factor affecting the signal recognition particle binding efficiency of nascent chains also affects targeting efficiency in a major way.…”

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

“…In mammals, CYPs have been found in the liver, brain, kidney, and many other tissues, and are primarily located in the endoplasmic reticulum, mitochondria, and plasma membrane compartments (Sangar et al, 2010).…”

“…Cytochrome P450 2A5 (CYP2A5) is a murine orthologue of the human nicotinemetabolizing enzyme CYP2A6 and is located primarily in the endoplasmic reticulum (ER) of the liver and olfactory mucosa of mice (Juvonen et al, 1985;Su et al, 1996;Piras et al, 2003;Sangar et al, 2010). CYP2A5 can be also found in mitochondrial membranes and the recent study suggests that mitochondrial CYP2A5 may play a role in the oxidative stress response (Honkakoski et al, 1988;Genter et al, 2006).…”

“…CYP2A5 is primarily located in the endoplasmic reticulum and mitochondrial membranes of the liver and olfactory mucosa of mice Su et al, 1996;Piras et al, 2003;Genter et al, 2006;Sangar et al, 2010). CYP2A5 is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins.…”

Comparative medicine

“…Recent studies show that these CYPs are also present in the mitochondrial compartment of human and rodent tissues (Sangar et al 2010). CYPs represent a superfamily of monooxigenases that play a pivotal role in drug metabolism (Fink-Gremmels 2008).…”