Presence Of Activation System Research Articles

In vivo DNA adduct formation by bisphenol A.

We have previously shown that bisphenol A (BPA) is oxidized to bisphenol-o-quinone in the presence of activation system and that the chemical reaction of DNA or deoxyguanosine 3'-monophosphate (dGMP) with bisphenol-o-quinone produces adducts. In the present study, using the 32P-postlabeling technique, we have investigated the in vivo DNA adduct formation by BPA by examining covalent modification in DNA. Administration of a single or multiple dose of 200 mg/kg of BPA to CD1 male rats produced two major and several minor adducts in liver DNA. The two major in vivo adducts matched the adduct profile of DNA or dGMP-bisphenol-o-quinone. To determine how BPA may be converted to DNA-binding metabolites, adducts were examined after incubation of DNA with BPA in the presence of a microsomal activation system. The in vitro incubation of BPA with DNA in the presence of a microsomal activation system revealed one major adduct and several minor adducts. The formation of adducts in DNA by BPA in the presence of a microsomal activation system was drastically decreased by known inhibitors of cytochrome P450. Adduct formation in DNA when cumene hydroperoxide or NADPH was used as a cofactor showed adducts with similar chromatographic mobilities as those from the reaction of dGMP-bisphenol-o-quinone. These data demonstrate that BPA is capable of binding covalently to DNA. DNA binding can be inhibited by the inhibitors of cytochrome P450. One of the DNA-binding metabolite(s) both in vitro and in vivo may be bisphenol-o-quinone. Covalent modifications in DNA by in vivo exposure of BPA may be a factor in the induction of hepatotoxicity.

Cytotoxic and mutagenic effects of sterigmatocystin on cultured Chinese hamster cells.

Cytotoxic and mutagenic effect of sterigmatocystin (STC), a carcinogenic mycotoxin, on cultured Chinese hamster cells were investigated in the presence or absence of a metabolic activation system. STC directly applied to the cells induced cytotoxicity and drug-resistant mutations in a time- and concentration-dependent manner. Analyses of the effects of STC showed that treatment for shorter periods was more effective than that for longer periods. The presence of an activation system, cytotoxic and mutagenic effects of STC were strongly enhanced, and 1% of the microsome fraction was most efficient in inducing the effects. Analyses by equitoxic comparison showed that there was little difference in mutagenic activity between the direct treatment and the treatment using an activation system.