Clinics and Research in Hepatology and Gastroenterology
Current trendIncreased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: Mechanisms and pathophysiological role
Section snippets
Role of cytochrome P450 2E1 in the biotransformation of drugs and endogenous compounds
CYP2E1 catalyses the biotransformation of numerous drugs used in the current pharmacopeia including acetaminophen (paracetamol), salicylic acid, halothane, isoflurane, isoniazid, theophylline and dapsone. Moreover, this enzyme metabolises ethanol, several industrial chemicals (e.g. carbon tetrachloride and vinyl chloride) as well as contaminants (e.g. nitrosamines and acrylamide) [11], [12]. Importantly, CYP2E1-mediated biotransformation of these compounds can generate toxic reactive
Cytochrome P450 2E1-mediated production of reactive oxygen species and other deleterious endogenous derivatives
In contrast to many other cytochromes P450, CYP2E1 is able to produce significant amounts of ROS (Fig. 1). Indeed, CYP2E1 generates superoxide anion and hydrogen peroxide during its catalytic cycle [15]. These ROS can subsequently damage unsaturated fatty acids, thus leading to lipid peroxidation and the generation of highly reactive aldehydes such as malondialdehyde and 4-hydroxynonenal (Fig. 1). ROS can also attack nucleic acids and proteins and induce mitochondrial membrane permeabilization,
Increased cytochrome P450 2E1 expression and activity in nonalcoholic fatty liver disease
A key feature of CYP2E1 is its inducibility, and consequently liver CYP2E1 levels can be enhanced in different pathophysiological conditions. A well-known condition of CYP2E1 induction is chronic alcohol intake. In this context, high CYP2E1 expression plays a key role in ethanol-induced oxidative stress, lipid peroxidation, mitochondrial dysfunction and hepatocyte injury [11], [20], [23]. CYP2E1 induction during chronic ethanol intake is most probably due to lower proteasomal degradation, thus
Nutritional and hormonal regulation of cytochrome P450 2E1
Fatty acids such as palmitic and oleic acids are able to increase CYP2E1 mRNA and/or protein levels in human hepatocytes or in differentiated human hepatoma HepaRG cells [45], [46]. Moreover, high-fat diets enhance CYP2E1 expression and activity in rat liver [27], [30], [47]. In one of these studies, hepatic CYP2E1 expression was increased only with the diet containing the highest levels of lipids (65%), but not when rats were fed a diet containing only 24% of fat and enriched in sucrose [30].
Pathophysiological consequences of increased cytochrome P450 2E1 expression in nonalcoholic fatty liver disease
As mentioned previously, CYP2E1 generates significant amounts of ROS that can subsequently induce lipid peroxidation and other oxidative damages (Fig. 1). A recent study in obese patients showed a significant association between CYP2E1 protein expression and lipid peroxidation levels in liver [39]. Several recent reviews have dealt with the role of ROS and lipid peroxidation in the pathophysiology of NAFLD, and especially regarding the progression of simple steatosis into NASH [2], [6], [8], [9]
Higher susceptibility to drug-induced liver injury in patients with nonalcoholic fatty liver disease
CYP2E1 induction in NAFLD could also favour drug-induced liver injury for several compounds metabolised by this enzyme (Fig. 2) [65]. For instance, obesity and NAFLD could increase the risk of acute hepatitis induced by the volatile halogenated anaesthetic halothane [66], [67] and the pain killer acetaminophen [68], [69].
Regarding acetaminophen intoxication, investigations in obese animals have given conflicting results. Whereas some studies showed increased hepatotoxicity [70], [71], others
Concluding remarks and perspectives
There is accumulating evidence for a physiopathological role of increased hepatic CYP2E1 expression in NAFLD. However, it is still unclear how this enzyme is deleterious for the liver in the absence of alcohol intoxication. Although a major mechanism could be ROS overproduction and subsequent oxidative alteration of key cellular components, CYP2E1 could also generate toxic derivatives through the oxidation of fatty acids. Moreover, it is still unknown whether CYP2E1 generates more ROS when
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
Acknowledgments
This work was supported by Institut nationale de la santé et de la recherche médicale (Inserm). Jacinthe Aubert was a recipient of a grant from ministère de L’Éducation Nationale, de la Recherche et de la Technologie, while Karima Begriche and Laetitia Knockaert were recipients of a grant from Région Bretagne.
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