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

Abstract

Background: Induced expression of CYP2E1 is known to enhance alcohol liver toxicity. Results: Novel mutations W23R/W30R and L32N in human CYP2E1 alter mitochondrial and microsomal targeting efficiency. Conclusion: Human variants with altered targeting modulate susceptibility of cells to alcohol. Significance: Carriers of the novel W23R/W30R mutation in CYP2E1 are likely to be more susceptible to alcohol toxicity.

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

“…In addition, the CYP2E1 inhibitor diallyl sulfide reversed the loss of complex IV activity and its subunits, probably via inhibition of CYP2E1-mediated oxidative stress. The same group further confirmed these results by using COS-7 cells and HepG2 cells stably expressing either the W23/30R mutant, which favorably targets CYP2E1 to mitochondria rather than ER, or the L32N variant, which preferentially directs CYP2E1 to ER than mitochondria [146]. Upon exposure to alcohol, the cells expressing the W23/30R mutant showed markedly increased ROS production, respiratory dysfunction, and loss of cytochrome c oxidase subunits (complex IV) with decreased activity compared to the cells expressing the L32N variant.…”

“…The presence of CYP2E1 isoforms in different cell compartments as illustrated by the elegant work of Avadhani group [135, 136, 138–140, 145, 146] triggers interesting questions some of which were previously raised by the same group: 1) Are microsomal and mitochondrial CYP2E1 work similarly to induce harmful effects or there is a distinctive function for each isoform? ; 2) Is there any specific sequential events or specific conditions that are unique for the activation of microsomal and mitochondrial CYP2E1 or they are activated simultaneously by the same inducers, most of which are CYP2E1 substrates?…”

1,3-Butadiene-induced mitochondrial dysfunction is correlated with mitochondrial CYP2E1 activity in Collaborative Cross mice

“…Since then, microsomal fractions or whole cell preparations have served as tools for studies assessing the impact of P450 activity on biological processes and thus, the foundations for toxicological mechanisms. Nevertheless, CYP2E1 is among a few of the microsomal P450s capable of expression in an active form within mitochondria(Avadhani et al 2011), yet mitochondrial CYP2E1 (mtCYP2E1) has only recently begun to be characterized for its metabolic properties(Hartman et al 2015; Robin et al 2002; Robin et al 2001) and its impact on normal cellular and mitochondrial functions (Abdelmegeed et al 2015; Bai and Cederbaum 2006; Bansal et al 2013; Bansal et al 2010). The sole expression of CYP2E1 in mitochondria of transfected HepG2 or COS-7 cells leads to higher levels of ROS and oxidative stress, mitochondrial dysfunction, and cytotoxicity, especially in the presence of acetaminophen or ethanol(Robin et al 2005; Sangar et al 2010).…”

The emerging theme of redox bioenergetics in health and disease

“…For example, functional associations of mitochondria with nitric oxide synthases, NADPH oxidase 4, and cytochrome P450 have recently been reported. [28][29][30] The functional significance of these interactions remains unclear in most cases. In this short overview, we will highlight this theme of redox bioenergetics and the articles supporting these developments from broader literature.…”