Cytochromes P450 in benzene metabolism and involvement of their metabolites and reactive oxygen species in toxicity
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
9118895
PubMed Central
PMC1469770
DOI
10.1289/ehp.961041211
Knihovny.cz E-resources
- MeSH
- DNA Adducts biosynthesis MeSH
- Benzene metabolism toxicity MeSH
- Benzoquinones metabolism toxicity MeSH
- Cytochrome P-450 CYP2E1 metabolism MeSH
- Hydroquinones metabolism toxicity MeSH
- Microsomes, Liver metabolism MeSH
- Rats MeSH
- Humans MeSH
- Oxidation-Reduction MeSH
- DNA Damage MeSH
- Rats, Wistar MeSH
- Proteins drug effects metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Benzene MeSH
- Benzoquinones MeSH
- Cytochrome P-450 CYP2E1 MeSH
- Hydroquinones MeSH
- hydroquinone MeSH Browser
- Proteins MeSH
- quinone MeSH Browser
- Reactive Oxygen Species MeSH
- Cytochrome P-450 Enzyme System MeSH
Cytochrome P450 (CYP) 2E1 was the most efficient CYP enzyme that oxidized benzene to soluble and covalently bound metabolites in rat and human liver microsomes. The covalent binding was due mostly to the formation of benzoquinone (BQ), the oxidation product of hydroquinone (HQ), and was inversely related to the formation of soluble metabolites. In rats, inhalation of benzene (4 mg/liter of air) caused a rapid destruction of CYP2B1 previously induced by phenobarbital. The ability of benzene metabolites to destroy liver microsomal CYP in vitro decreased in the order BQ > HQ > catechol > phenol. The destruction was reversed by ascorbate and diminished by alpha-tocopherol, suggesting that HQ was not toxic, whereas BQ and semiquinone radical (SQ) caused the effect. In the presence of nicotinamide adenine dinucleotide phosphate, reduced (NADPH) the microsomes did not oxidize HQ to BQ, while the formation of superoxide anion radical from both HQ and BQ was markedly quenched. Destruction of CYP in vitro caused by HQ or BQ was not mediated by hydroxyl radical formation or by lipid peroxidation. On the contrary, HQ and BQ inhibited NADPH-mediated lipid peroxidation. Ascorbate induced high levels of hydroxyl radical formation and lipid peroxidation, which were differentially affected by quinones, indicating different mechanisms. Despite reducing the toxicity of HQ and BQ, ascorbate appeared to induce its own toxicity, reflected in high levels of lipid peroxidation. Iron redox cycling played a significant role in the NADPH-induced hydroxyl radical formation but not in that caused by ascorbate; however, lipid peroxidation induced by NADPH or ascorbate was suppressed by ethylenediaminetraacetate, indicating a crucial role of iron. Thus, the data indicate that the quinones destroyed CYP directly and not via oxygen activation or lipid peroxidation.
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