Biomarkers of effect in evaluating dithianon cocarcinogenesis: selective induction and suppression of murine CYP3A isoform.

Abstract

The ability of dithianon, whose mutagenic/cocarcinogenic activity has as yet not been clarified, to affect specific biomarkers of effect related to non-genotoxic cocarcinogenesis was investigated. For this purpose, several CYP-dependent reactions have been studied in liver, kidney and lung microsomes derived from male and female Swiss Albino CD1 mice treated i.p. with single (3 or 6 mg kg(-1) b.w.) or repeated (3 mg kg(-1) b.w., daily for 3 days) administrations of such fungicide. No significant changes in both absolute and relative liver, kidney and lung weights were achieved after dithianon treatment. Whereas a single dose was able to significantly induce certain monooxygenases, with repeated treatments a loss of activity was observed. For example, a approximately 2.4-fold increase of CYP3A-dependent activity, probed by N-demethylation of aminopyrine, was achieved in the liver (both sexes, lower dose) and, to a lesser extent, in lung. A small, but significant increase in the hydroxylation of p-nitrophenol (2E1) and in the O-deethylation of ethoxycoumarin (mixed) was also found in liver. With the exception of a approximately 46% loss in the 3A-like activity, no appreciable changes of the selected biomarkers were observed in kidney. Repeated dithianon doses were able to significantly reduce the 3A- and 2E1-dependent monooxygenases (approximately 30% and approximately 30% loss, respectively, averaged between male and female), as well as ethoxycoumarin O-deethylase activity (approximately 54% loss) in the liver. On the contrary, no significant CYP modulation in both kidney and lung was recorded. On the whole, dithianon has a complex pattern of CYP induction or suppression in various tissues of both sexes, suggesting the possible toxic/cotoxic and cocarcinogenic potential of this fungicide. These data can contribute to a better understanding of its toxicological profile, providing more information concerning the risk associated to human exposure.