The Metabolic Rate Constants and Specific Activity of Human and Rat Hepatic Cytochrome P-450 2E1 Toward Toluene and Chloroform

Lipscomb, John C.; Barton, Hugh A.; Tornero‐Velez, Rogelio; Evans, Marina V.; Alcasey, Sattar; Snawder, John E.; Laskey, John W.

doi:10.1080/15287390490425588

Cited by 26 publications

(13 citation statements)

References 21 publications

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“…Cytochrome P450 2e1 (the CYP2E1 protein product) has be highest affinity for THMs (K m = 0.15 µM) and has a high maximum rate of catalysis (V max = 28.3 nmol/h/mg protein) (Lipscomb et al, 2004). At an oral dose equivalent to 72 µg/kg, peak concentrations of BDCM in blood were 2.6 ng/L (equivalent to 0.016 nM) and 90.5 ng/L (0.76 nM) from a dermal exposure of an hour to a dose-equivalent concentration were observed in human volunteers (Leavens et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines

Bull¹,

et al. 2011

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Drinking water disinfectants react with natural organic material (NOM) present in source waters used for drinking water to produce a wide variety of by-products. Several hundred disinfection by-products (DBPs) have been identified, but none have been identified with sufficient carcinogenic potency to account for the cancer risks projected from epidemiological studies. In a search for DBPs that might fill this risk gap, the present study projected reactions of chlorine and chloramine that could occur with substructures present in NOM to produce novel by-products. A review of toxicological data on related compounds, supplemented by use of a quantitative structure toxicity relationship (QSTR) program TOPKAT® identified chemicals with a high probability of being chronically toxic and/or carcinogenic among 489 established and novel DBPs. Classes of DBPs that were specifically examined were haloquinones (HQs), related halo-cyclopentene and cyclohexene (HCP&H) derivatives, halonitriles (HNs), organic N-chloramines (NCls), haloacetamides (HAMs), and nitrosamines (NAs). A review of toxicological data available for quinones suggested that HQs and HCP&H derivatives appeared likely to be of health concern and were predicted to have chronic lowest observed adverse effect levels (LOAELs) in the low μg/kg day-1 range. Several HQs were predicted to be carcinogenic. Some have now been identified in drinking water. The broader class of HNs was explored by considering current toxicological data on haloacetonitriles and extending this to halopropionitriles. 2,2-Dichloropropionitrile has been identified in drinking water at low concentrations, as well as the more widely recognized haloacetonitriles. The occurrence of HAMs has been previously documented. The very limited toxicological data on HAMs suggests that this class would have toxicological potencies similar to the dihaloacetic acids. Organic N-halamines are also known to be produced in drinking water treatment and have biological properties of concern, but no member has ever been characterized toxicologically beyond bacterial or in vitro studies of genotoxicity. The documented formation of several nitrosamines from secondary amines from both natural and industrial sources prompted exploration of the formation of additional nitrosamines. N-Diphenylnitrosamine was identified in drinking waters. Of more interest, however, was the formation of phenazine (and subsequently N-chorophenazine) in a competing reaction. These are the first heterocyclic amines that have been identified as chlorination by-products. Consideration of the amounts detected of members of these by-product classes and their probable toxicological potency suggest a prioritization for obtaining more detailed toxicological data of HQs > HCP&H derivatives > NCls > HNs. Based upon a ubiquitous occurrence and virtual lack of in vivo toxicological data, NCls are the most difficult group to assign a priority as potential carcinogenic risks. This analysis indicates that research on the general problem of DBPs re...

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Section: Discussionmentioning

confidence: 99%

Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines

Bull¹,

et al. 2011

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“…Reaction with cysteine is also reported. The oxidation of chloroform is catalyzed mainly by CYP2E1 (and also by CYP2A6 and other CYPs) to produce the hydroxylated analog as an unstable metabolite [187] [188]. These proteins have molecular weights in the range 3.5 -14 kDa and contain ca.…”

Section: Fig 548mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Testa

Kraemer

2009

ChemInform

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The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

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“…at ASPET Journals on May 12, 2018 dmd.aspetjournals.org metabolic rates for CYP2E1 substrates depend on the CYP2E1 content of the preparation or system under investigation and therefore cannot be based on differences in the intrinsic activity of the enzyme between these species (Lipscomb et al, 2004). In this study, we have shown a difference in the hydroxylation of p-nitrophenol to p-nitrocatechol between wild-type and CYP2E1-humanized mice, suggesting a potential species difference in substrate metabolism, although chlorzoxazone metabolism was similar.…”

Section: Human Cyp2e1 Expression In Transgenic Micementioning

confidence: 99%

THECYP2E1-HUMANIZED TRANSGENIC MOUSE: ROLE OF CYP2E1 IN ACETAMINOPHEN HEPATOTOXICITY

et al. 2004

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ABSTRACT:The cytochrome P450 (P450) CYP2E1 enzyme metabolizes and activates a wide array of toxicological substrates, including alcohols, the widely used analgesic acetaminophen, acetone, benzene, halothane, and carcinogens such as azoxymethane and dimethylhydrazine. Most studies on the biochemical and pharmacological actions of CYP2E1 are derived from studies with rodents, rabbits, and cultured hepatocytes; therefore, extrapolation of the results to humans can be difficult. Creating "humanized" mice by introducing the human CYP2E1 gene into Cyp2e1-null mice can circumvent this disadvantage. A transgenic mouse line expressing the human CYP2E1 gene was established. Western blot and high-performance liquid chromatography/mass spectrometry analyses revealed human CYP2E1 protein expression and enzymatic activity in the liver of CYP2E1-humanized mice. Treatment of mice with the CYP2E1 inducer acetone demonstrated that human CYP2E1 was inducible in this transgenic model. The response to the CYP2E1 substrate acetaminophen was explored in the CYP2E1-humanized mice. Hepatotoxicity, resulting from the CYP2E1-mediated activation of acetaminophen, was demonstrated in the livers of CYP2E1-humanized mice by elevated serum alanine aminotransferase levels, increased hepatocyte necrosis, and decreased P450 levels. These data establish that in this humanized mouse model, human CYP2E1 is functional and can metabolize and activate different CYP2E1 substrates such as chlorzoxazone, p-nitrophenol, acetaminophen, and acetone. CYP2E1-humanized mice will be of great value for delineating the role of human CYP2E1 in ethanol-induced oxidative stress and alcoholic liver damage. They will also function as an important in vivo tool for predicting drug metabolism and disposition and drug-drug interactions of chemicals that are substrates for human CYP2E1.The cytochrome P450 (P450) family of enzymes play an important role in the metabolic activation of chemicals to cytotoxic or carcinogenic products, as well as the oxidation of therapeutically used drugs and endogenous steroids (Guengerich et al., 1991;Lieber, 1997). In particular, CYP2E1 is of interest since it metabolizes and activates a wide array of toxicologically important substrates, including acetaminophen (APAP), acetone, benzene, halothane, ethanol, carbon tetrachloride, and carcinogens such as the low molecular weight nitrosamines (Kessova and Cederbaum, 2003). CYP2E1 metabolizes a small number of clinically employed drugs such as disulfiram and the muscle relaxant chlorzoxazone, which undergoes 6-hydroxylation (Peter et al., 1990;Carriere et al., 1993). CYP2E1 also oxidizes a significant number of important occupational and industrial chemicals, including alkanes, alkenes, solvents, and aromatic and halogenated hydrocarbons (Bolt et al., 2003).APAP is a widely used analgesic and is considered safe at therapeutic doses; hepatotoxicity occurs at low frequency. Metabolism of APAP was shown to be primarily contributed by CYP2E1 (Raucy et al., 1989;Snawder et al., 1994a;Kostrubsky et al...

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The Metabolic Rate Constants and Specific Activity of Human and Rat Hepatic Cytochrome P-450 2E1 Toward Toluene and Chloroform

Cited by 26 publications

References 21 publications

Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines

Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

THECYP2E1-HUMANIZED TRANSGENIC MOUSE: ROLE OF CYP2E1 IN ACETAMINOPHEN HEPATOTOXICITY

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