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.

• MeSH
• adukty DNA biosyntéza   MeSH
• benzen metabolismus   toxicita   MeSH
• benzochinony metabolismus   toxicita   MeSH
• cytochrom P-450 CYP2E1 metabolismus   MeSH
• hydrochinony metabolismus   toxicita   MeSH
• jaterní mikrozomy metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• oxidace-redukce MeSH
• poškození DNA MeSH
• potkani Wistar MeSH
• proteiny účinky léků   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• benzen MeSH
• benzochinony MeSH
• cytochrom P-450 CYP2E1 MeSH
• hydrochinony MeSH
• hydroquinone MeSH Prohlížeč
• proteiny MeSH
• quinone MeSH Prohlížeč
• reaktivní formy kyslíku MeSH
• systém (enzymů) cytochromů P-450 MeSH

Benzene (B), toluene (T), ethylbenzene (EB), styrene (S) and xylene isomers (oX, mX, pX) are important environmental pollutants and B is a proved human carcinogen. Their inhalation by male Wistar rats (4 mg/l, 20 h/day, 4 days) caused cytochrome P450 (P450) induction. The degree of P450 2B1 induction increased and that of 2E1 decreased in the series B, T, EB, S, oX, mX and pX, as estimated by Western blots, while neither solvent was as effective for 2B1 induction as phenobarbital and B was more effective for 2E1 than ethanol. The levels of several other P450s decreased after exposure to these solvents, B being most effective. Exposure to these solvents increased in vitro hepatic microsomal oxidation of B and aniline (AN) (2E1 substrates) 3 to 6-fold, indicating induction of this P450. T oxidation was increased 2 to 4-fold and chlorobenzene (ClB) oxidation 3-fold. Sodium phenobarbital (PB, 80 mg/kg/day, 4 days, i.p.) did not increase ethylmorphine (EM) and benzphetamine (BZP) demethylation (2B1 substrates), neither of the B derivatives did so, and oX decreased it; however, pentoxyresorufin O-dealkylation was well related to the immunochemically detected 2B1 levels in control, PB and B microsomes. PB did not increase B, but increased T and ClB oxidation 2-4 and 3-fold, respectively, indicating possible 2B1 role in their oxidation. B oxidation after various inducers was related to immunochemical 2E1 levels, T and ClB oxidation to both 2B1 and 2E1 and AN oxidation to 2E1 and 1A2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

• MeSH
• benzen metabolismus   toxicita   MeSH
• cytochrom P-450 CYP2B1 MeSH
• cytochrom P-450 CYP2E1 MeSH
• enzymová indukce účinky léků   MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• krysa rodu Rattus MeSH
• N-demethylasy biosyntéza   MeSH
• oxidoreduktasy biosyntéza   MeSH
• potkani Wistar MeSH
• systém (enzymů) cytochromů P-450 biosyntéza   MeSH
• toluen toxicita   MeSH
• xyleny toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzen MeSH
• cytochrom P-450 CYP2B1 MeSH
• cytochrom P-450 CYP2E1 MeSH
• N-demethylasy MeSH
• oxidoreduktasy MeSH
• systém (enzymů) cytochromů P-450 MeSH
• toluen MeSH
• xyleny MeSH