BIOMARKERS OF EFFECT IN EVALUATING DITHIANON COCARCINOGENESIS - SELECTIVE INDUCTION AND SUPPRESSION OF MURINE CYP3A ISOFORM

The ability of dithianon, whose mutagenic/cocarcinogenic activity has as yet not been clarified, to affect specific biomarkers of effect rel ated to non-genotoxic cocarcinogenesis was investigated. For this purp ose, several CYP-dependent reactions have been studied in liver, kidne y and lung microsomes derived from male and female Swiss Albino CD1 mi ce 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 s ignificant changes in both absolute and relative liver, kidney and lun g weights were achieved after dithianon treatment. Whereas a single do se was able to significantly induce certain monooxygenases, with repea ted treatments a loss of activity was observed. For example, a similar to 2.4-fold increase of CYP3A-dependent activity, probed by N-demethy lation of aminopyrine, was achieved in the liver (both sexes, lower do se) and, to a lesser extent, in lung. A small, but significant increas e in the hydroxylation of p-nitrophenol (2E1) and in the O-deethylatio n of ethoxycoumarin (mixed) was also found in liver. With the exceptio n of a similar to 46% loss in the 3A-like activity, no appreciable cha nges of the selected biomarkers were observed in kidney. Repeated dith ianon doses were able to significantly reduce the 3A- and 2E1-dependen t monooxygenases (similar to 30% and similar to 30% loss, respectively , averaged between male and female), as well as ethoxycoumarin O-deeth ylase activity (similar to 54% loss) in the liver. On the contrary, no significant CYP modulation in both kidney and lung was recorded. On t he whole, dithianon has a complex pattern of CYP induction or suppress ion in various tissues of both sexes, suggesting the possible toxic/co toxic and cocarcinogenic potential of this fungicide. These data can c ontribute to a better understanding of its toxicological profile, prov iding more information concerning the risk associated to human exposur e.