Production of DNA strand breaks by N-nitrosodimethylamine and 2-amino-3-methylimidazo[4,5-f]quinoline in THLE cells expressing human CYP isoenzymes and inhibition by sulforaphane.
The production of DNA strand breaks by N-nitrosodimethylamine (NDMA) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) has been observed in T5-2E1 (expressing human CYP2E1) and T5-1A2 (expressing human CYP1A2) human liver cells respectively, using the Comet assay. Responses were statistically significant (P<0.05) and concentration dependent (0.01-1 microg ml-1 NDMA and 0.1-10 microg ml-1 IQ) and were not observed in T5-neo cells devoid of cytochrome P450 activity. Sulforaphane (1-isothiocyanate-4-methylsulfinylbutane) (0.1-10 microM) gave a marked inhibition of DNA strand breakage by these carcinogens (P<0.05 linear regression). This was seen in the absence of cytotoxicity and in the absence of an inhibition of H2O2-induced DNA strand breakage. The ability of sulforaphane to inhibit both CYP2E1 and CYP1A2-mediated genotoxicity therefore is relevant to human isoforms of these enzymes and may contribute to a chemopreventative activity.
Department of Pharmaceutical Sciences, Aston University, Birmingham B4 7ET, UK.
S
S
Barceló
K
K
Macé
A M
AM
Pfeifer
J K
JK
Chipman
D016587:Antimutagenic Agents / Q000494:pharmacology*; D002460:Cell Line; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004249:DNA Damage; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017879:Isothiocyanates; D009153:Mutagens / Q000633:toxicity*; D011804:Quinolines / Q000633:toxicity*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*
D016587:Antimutagenic Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D009153:Mutagens; D011804:Quinolines; D013454:Sulfoxides; D013861:Thiocyanates; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; C016766:sulforaphane; D004128:Dimethylnitrosamine