Induction and suppression of murine CYP-mediated biotransformation by dithianon: organ- and sex-related differences.
With the aim of evaluating the co-carcinogenic properties of dithianon, the regio- and stereo-selective hydroxylation of testosterone was used as a multibiomarker of effect for cytochrome P450 ( CYP) changes. CYP-catalysed reactions have been studied in liver, kidney and lung microsomes from male and female Swiss albino CD1 mice treated i.p. with single (3 or 6 mg/kg body wt.) or repeated (3 mg/kg body wt. daily for 3 days) doses of this fungicide. Induction or suppression was recorded under various situations in different organs and sexes. In liver, all testosterone hydroxylase ( TH) activities were increased in the single treatment from 2.8- (6beta-, 16alpha- and 16beta- TH activities) to 16-fold (2beta- TH activity) in males at the lower dose. In contrast, activities were reduced from 33.3% (16beta- and 17- TH activities, lower dose) to 66.4% (16beta- TH activity, higher dose) in females. In kidney, a similar pattern of modulation was achieved: induction from 2.9- to 5-fold (6beta- and 2alpha- TH activities, higher and lower doses, respectively) in males; suppression from 47.4 to 50.2% (2alpha- and 2beta- TH activities, either at lower or higher doses) in females. In lung, a significant induction ranging from 7.1- to 29.3-fold (16alpha- and 2alpha- TH activities, respectively, lower dose) in males, and up to a 7-fold increase (2beta- TH activity, higher dose) in females was obtained. After repeated treatment, hepatic 6beta-, 16beta-, 2alpha- and 2beta- TH activities were reduced up to approximately 60% in males, whereas no effect was seen in females. In extrahepatic tissues, a generalized increase of different THs was observed. The increase of 6beta- TH activity (CYP3A-linked), one of the most representative isoforms in humans, was sustained in liver and kidney by means of Western immunoblotting, using rabbit polyclonal antibodies anti CYP3A1/2. On the whole, a complex pattern of induction/suppression of CYP-dependent reactions was achieved depending on sex and tissue. The data are consistent with co-toxic, co-carcinogenic and promoting potentials of this fungicide and provide information of interest in evaluating the risk associated with human exposure.[1]References
- Induction and suppression of murine CYP-mediated biotransformation by dithianon: organ- and sex-related differences. Pozzetti, L., Paolini, M., Barillari, J., Cantelli-Forti, G. Cancer Lett. (1999) [Pubmed]
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