Journal Article

CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane

Silvia Barcelo, John M. Gardiner, Andreas Gescher and J.Kevin Chipman

in Carcinogenesis

Volume 17, issue 2, pages 277-282
Published in print February 1996 | ISSN: 0143-3334
Published online February 1996 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/17.2.277
CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane

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The broccoli constituent sulforaphane (1-isothiocyanate-4-methylsulfinylbutane) has previously been shown to protect rats against 9, 10-dimethyl-1, 2-benz[a]anthracene tumori-genesis, thought to be due, at least in part, to induction of phase II detoxification. We investigated the ability of sulforaphane to also inhibit the phase I enzyme cytochrome P450 isoenzyme 2E1 (CYP2E1), which is responsible for activation of several carcinogens, including dialkylnitros-amines. Using the p-nitrophenol hydroxylation assay in microsomes from livers of acetone-treated Sprague-Dawley rats, sulforaphane was shown to be a potent competitive inhibitor of CYP2E1 with a K1pg of 347.0 ± 4.5 μM. In view of this result, we studied the capacity of sulforaphane to inhibit the genotoxicity of N-nitrosodimethylamine (NDMA). Sulforaphane at concentrations of >0.8 μM inhibited the mutagenicity of NDMA (4.4 mg/plate) in Salmonella typhimurium strainDTA100 after pre-incubation for 45 min with cytosol extract from livers of Balb/c mice pre-treated with acetone. Unsecheduled DNA synthesis induced by NDMA (33.5 μM)in mouse hepatocytes was inhibited in a dose-dependent manner by sulforaphane at 0.064–20 μM. Sulforaphane was unable to inhibit mutagenicity of sodium azide (5 μg/plate), a direct acting mutagen, in the Salmonella assay. It was not itself genotoxic in hepatocytes, as measured by unscheduled DNA synthesis, or mutagenic in the strain of Salmonella employed and cytotoxic only at high concentrations (≧0.5 mM). These findings suggest that inhibition of CYP2E1 by sulforaphane may offer chemoprotection against carcinogenic substrates of this enzyme.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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