Cyp2e1

Abstract

ABSTRACT:Bernard B. Brodie's laboratory was the first to examine the mechanisms of drug-induced toxicity at the molecular level. They found that acetaminophen hepatotoxicity was due to the metabolic activation of the drug to a highly reactive toxic metabolite that depleted cellular glutathione and covalently bound to protein. Subsequent studies revealed that activation of acetaminophen to an active metabolite is primarily carried out by CYP2E1, an ethanolinducible cytochrome P450 that was first suggested by characterization of the microsomal ethanol oxidation system. CYP2E1 is developmentally regulated, under liver-specific control, and undergoes substrate-induced protein stabilization. It is also regulated by starvation and diabetes through insulin-dependent mRNA stabilization. In addition to acetaminophen, CYP2E1 metabolically activates a large number of low M r toxicants and carcinogens and thus is of great toxicological importance. The mechanism of regulation CYP2E1 and its role in acetaminophen toxicity will be discussed.I am delighted and honored to be a recipient of the Bernard B. Brodie award. Like Brodie, I have spent my career at the National Institutes of Health. Other than our mutual interest in xenobiotic metabolism, the similarities end. Brodie was a pioneer in drug metabolism and toxicity and the concepts he generated during the course of his career are still of major importance in the development and use of drugs, and in the fields of dietary and environmental toxicology. Brodie led the transition of the field of classical physiological-based pharmacology into biochemical pharmacology where mechanism of drug action and toxicity could be determined. In particular, he noted that drug-induced toxicities can be due to dose-dependent production of highly reactive and unstable intermediates that covalently bind to cellular macromolecules. These concepts laid the foundations for subsequent studies including the enzymology, purification, and cloning of drug-metabolizing enzymes and, more recently, the production of genetically modified mice that were used to reveal the in vivo role of P450s and other drug-metabolizing enzymes in chemical toxicities. Among the most important P450s involved in chemical toxicities is CYP2E1. Ethanol-Inducible CYP2E1CYP2E1 has been extensively studied for many years because of its relevance to chemical toxicity and carcinogenicity. It is also conserved in mammals; although there are a number of single nucleotide polymorphisms in the CYP2E1 gene, there are no known polymorphisms that are the result of inactive CYP2E1 genes in humans or any animal models, and there are no large differences in catalytic activity among humans, rabbits, rats, and mice. This suggests that CYP2E1 has an important function in mammals.The Microsomal Ethanol Oxidation System and CYP2E1. The finding that microsomal membrane fractions are capable of catalyzing the oxidation of ethanol, designated the microsomal ethanol-oxidizing system (MEOS), was the first indication of the presence of an ethanol oxidi...

CYP2E1 RsaI/PstI Polymorphism and Liver Cancer Risk among East Asians: a Huge Review and Meta-analysis

“…Human CYP2E1 also involved in the formation of glycidamide from acrylamide for glycidamide is suspected of being the ultimate carcinogenic metabolite of acrylamide (Settels et al, 2008). In addition, CYP2E1 plays an important role in the metabolize of acetaminophen (APAP), which is a common cause of drug-induced hepatotoxicity if overdosed (Gonzalez, 2007). In the subgroup analysis by country, we observed significant associations between CYP2E1 RsaI/PstI polymorphism and decreased risk of liver cancer among Chinese.…”

“…Although the exact function of RsaI/PstI polymorphism in tumorigenesis of liver was not clear yet, a possible reason is that the mutations of RsaI/PstI polymorphism may influence the CYP2E1 enzyme metabolizes and activates toxicological substrates (Cheung et al, 2005). CYP2E1 metabolically activates a large number of toxicants and carcinogens and thus is of great toxicological importance (Gonzalez, 2007). Recent study revealed that inhibition of CYP2E1 would led to significant decreases in high glucose mediated oxidative stress and toxicity (Chandrasekaran et al, 2012).…”

Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase

“…In one, APAP detoxification is regulated by the central circadian clock that regulates feeding schedules which directly drive glutathione levels and indirectly drive some P450 activities (Cyp2e1) in the liver (11,12). In the other, the hepatocyte circadian clock regulates the transcription of genes involved in APAP oxidation.…”

“…Although the importance of glutathione is often emphasized, it also has been proposed that variations in cytochrome P450 activity may be important in chronotoxicity (10). In this regard, ketones generated during the fasting phase have been proposed to increase levels of a specific APAP-metabolizing cytochrome P450, such as CYP2E1, presumably via ligand stabilization (11,12). Collectively, these data have led to the idea that feeding-and fasting-driven oscillations in glutathione and the cytochromes P450 are major determinants of APAP chronotoxicity in the liver.…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…However, a small amount of APAP is oxidized to the reactive metabolite N‐acetyl‐ p ‐benzoquinone imine (NAPQI) by CYPs 2E1 (CYP2E1) and 3A4 (Gonzalez 2007; Aubert et al. 2012).…”