CYP2E1

Few drugs are metabolized by CYP2E1, but it plays a major role in the metabolism of numerous halogenated hydrocarbons (including volatile general anesthetics) and a range of low-molecular-weight organic compounds, including dimethyformamide, acetonitrile, acetone, ethanol, and benzene, as well as in the activation of acetaminophen to its reactive metabolite, N-acetyl-p-benzoquinoneimine). The CYP2E1 is of most interest because of the toxicity and carcinogenicity of its metabolites. This isoform is expressed in the liver (7%), kidney, intestine, and lung, and it is inducible by ethanol, isoniazid, 4-methylpyrazole, and other chemicals. It also is known as microsomal ethanol-oxidizing system, benzene hydroxylase, or aniline hydroxylase. The CYP2E1 is induced in alcoholics, and there is a polymorphism associated with this isoform that is more common in Chinese people.
This isoform also appears to be related to smoking-induced cancer (c.f., CYP1A2). Most of the same compounds that induce CYP2E1 also are substrates for the enzyme. The induction of this enzyme in humans can cause enhanced susceptibility to the toxicity and carcinogenesis of CYP2E1 substrates. Some evidence shows interindividual variation in the in vitro liver expression of this isoform. Diabetes and dietary alterations (i.e., fasting and obesity) result in the induction of CYP2E1. Ketogenic diets (increased serum ketone levels), including those deficient in carbohydrates or high in fat, are known to enhance the metabolism of halogenated hydrocarbons in rats. The mechanism of induction appears to be a combination of an increase in CYP2E1 transcription, mRNA translation efficiency, and stabilization of CYP2E1 against proteolytic degradation. The induction of CYP2E1 resulting from ketosis (i.e., starvation, a high-fat diet, uncontrolled diabetes, and obesity) or exposure to alcoholic beverages or other xenobiotics may be detrimental to individuals simultaneously exposed to halogenated hydrocarbons (increased hepatotoxicity from exposure to halothane, chloroform). Chronic alcohol intake is known to enhance the hepatotoxicity of halogenated hydrocarbons. Testosterone appears to regulate CYP2E1 levels in the kidney and pituitary growth hormone for regulating hepatic levels of CYP2E1. Kidney damage from halocarbons was greater for male rats but not for female rats. This finding may have implications for sexual differences in the nephrotoxicity of CYP2E1 substrates in humans.