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Title: Cytochromes P450 in benzene metabolism and involvement of their metabolites and reactive oxygen species in toxicity

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 K mgAiter of air caused a rapid destruction of CYP281 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 BO and serniquinone radical (SO) caused the effect. In the presence of nicotinamide adenine clinucleoticle 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 peroxiclation. 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 bymore » 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 peroxiclation. Iron redox cycling played a significant role in the NADPH-induced hydroxyl radical formation but not in that caused by ascorbate; however, lipid peroxiclation 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 peroxiclation. 35 refs., 9 figs., 3 tabs.« less
Authors:
; ;  [1]
  1. National Institute of Public Health, Praha (Czech Republic) [and others
Publication Date:
OSTI Identifier:
472162
Report Number(s):
CONF-9506288--
Journal ID: EVHPAZ; ISSN 0091-6765; CNN: Grant 0260-4;Grant 0955-3;Grant 2763-4; TRN: 97:001626-0014
Resource Type:
Journal Article
Resource Relation:
Journal Name: Environmental Health Perspectives; Journal Volume: 104; Journal Issue: Suppl.6; Conference: Benzene `95: international conference on benzene toxicity, carcinogenesis, and epidemiology, Piscataway, NJ (United States), 17-20 Jun 1995; Other Information: PBD: Dec 1996
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
02 PETROLEUM; 55 BIOLOGY AND MEDICINE, BASIC STUDIES; 56 BIOLOGY AND MEDICINE, APPLIED STUDIES; BENZENE; METABOLISM; QUINONES; OXIDATION; LIPIDS; ASCORBIC ACID; BIOCHEMISTRY; CYTOCHROMES; INHALATION; MICROSOMES; NICOTINAMIDE; PHENOBARBITAL; RATS; TOXICITY; OCCUPATIONAL EXPOSURE; EXHAUST GASES; AIR POLLUTION; PETROLEUM REFINERIES; HYDROXYL RADICALS