Kinetic factors involved in the metabolism of benzene in mouse lung and liver

Patrick L. Sheets, Gary P. Carlson

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Benzene is an occupational and environmental toxicant. The main human health concern associated with benzene exposure is acute myelogenous leukemia. Benzene produces lung tumors in mice, while its effects on human lung are not clear. The adverse effects of benzene are dependent on its metabolism by the cytochrome P-450 enzyme system. The isozymes CYP2E1 and CYP2F2 play roles in the metabolism of benzene at low, environmentally relevant concentrations. Previous studies indicate that the mouse lung readily metabolizes benzene and that CYP2F2 plays a role in this biotransformation. The significance of CYP2E1 and CYP2F2 in benzene metabolism was determined by measuring their apparent kinetic parameters Km and Vmax. Use of wild-type and CYP2E1 knockout mice and selective inhibitors allowed the determination of the individual importance of both CYP2E1 and CYP2F2 in mouse liver and lung. A simple Michaelis–Menten relationship involving Lineweaver–Burk plots for the microsomal metabolism of benzene shows the apparent kinetic factors are different between the wild-type (Km: 30.4 μM, Vmax: 25.3 pmol/mg protein/min) and knockout (Km: 1.9 μM, Vmax: 0.5 pmol/mg protein/min) mouse livers. Wild-type lung has a Km of 2.3 μM and Vmax of 0.9 pmol/mg protein/min. CYP2E1 knockout lung has similar affinity and metabolic activity with a Km of 3.7 μM and Vmax of 1.2 pmol/mg protein/min. These data suggest CYP2E1 is less important in the lung than liver, and that it has a lower affinity for benzene but higher rate of hydroxylated metabolite production than does CYP2F2, which plays the predominant role in metabolizing benzene in mouse lung.

Original languageEnglish (US)
Pages (from-to)421-430
Number of pages10
JournalJournal of Toxicology and Environmental Health - Part A
Volume67
Issue number5
DOIs
StatePublished - Mar 2004
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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