CYP2E1, a cytochrome P-450 that is well conserved across mammalian species, metabolizes ethanol and many low molecular weight toxins and cancer suspect agents. The cyp2e1 gene was isolated, and a mouse line that lacks expression of CYP2E1 was generated by homologous recombination in embryonic stem cells. Animals deficient in expression of the enzyme were fertile, developed normally, and exhibited no obvious phenotypic abnormalities, thus indicating that CYP2E1 has no critical role in mammalian development and physiology in the absence of external stimuli. When cyp2e1 knockout mice were challenged with the common analgesic acetaminophen, they were found to be considerably less sensitive to its hepatotoxic effects than wild-type animals, indicating that this P-450 is the principal enzyme responsible for the metabolic conversion of the drug to its active hepatotoxic metabolite.Cytochromes P-450 (P-450) 1 are a superfamily of hemoproteins that carry out oxidative metabolism of many endogenous and foreign chemicals (1). In mammals, P-450s can be functionally segregated into two groups, those that participate in biochemical pathways leading to the synthesis of steroid hormones and those that primarily metabolize foreign chemicals or xenobiotics such as drugs. The latter enzymes are included in the CYP1, CYP2, CYP3, and CYP4 families (2). Many of the hepatic xenobiotic-metabolizing P-450s also metabolize endogenous compounds, but the significance of these reactions is questionable. A clue to the lack of a critical role for many of the P-450s, particularly those in family 2, in development, reproduction, and longevity, is the marked species differences in their expression and catalytic activities (3). However, some of the xenobiotic-metabolizing P-450s are well conserved, including those in the CYP1 family and CYP2E1, suggesting that they may perform an important physiological function.CYP2E1 is the principal P-450 responsible for the metabolism of ethanol and is considered as a major component of the microsomal ethanol-oxidizing system (4, 5). Among xenobiotics metabolized by CYP2E1 are acetaldehyde, acetaminophen, acrylamide, aniline, benzene, butanol, carbon tetrachloride, diethylether, dimethyl sulfoxide, ethyl carbamate, ethylene chloride, halothane, glycerol, ethylene glycol, N-nitrosodimethylamine, 4-nitrophenol, pyrazole, pyridine, and vinyl chloride (6). Many of these chemicals are known toxins, established chemical carcinogens, or suspected carcinogens. CYP2E1-mediated oxidation of a variety of substrates is also believed to liberate a substantial amount of reactive oxygen that can lead to membrane lipid peroxidation and cell toxicity (7).CYP2E1 is also capable of metabolizing endogenous chemicals including acetone and acetol, which are key metabolites in the methylglyoxal and propanediol pathways of gluconeogenesis (8, 9). CYP2E1 can also carry out the metabolism of arachidonic acid, resulting in the production of several hydroxyeicosatetraenoic acids (10), some of which may have physiological and pharmacol...
Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.
The aryl hydrocarbon (dioxin) receptor (AhR) has been studied for several decades largely because of its critical role in xenobiotic-induced toxicity and carcinogenesis. Albeit this is a major issue in basic and clinical research, an increasing number of investigators are turning their efforts to try to understand the physiology of the AhR under normal cellular conditions. This is an exciting area that covers cell proliferation and differentiation, endogenous mechanisms of activation, gene regulation, tumor development and cell motility and migration, among others. In this review, we will attempt to summarize the studies supporting the implication of the AhR in those endogenous cellular processes.
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