Testosterone hydroxylase as multibiomarker of effect in evaluating vinclozolin cocarcinogenesis.

In this work the modulation of the regio- and stereo-selective hydroxylation of testosterone by vinclozolin was studied in evaluating cocarcinogenic properties. Changes of cytochrome P450-(CYP)-catalysed drug metabolism was investigated in liver, kidney and lung microsomes of Swiss Albino CD1 mice of both sexes after single (625 or 1250 mg kg-1 b.w.) or repeated (daily 750 mg kg-1 b.w. for 3 days) i.p. administrations. Treatment of mice with a single dose of vinclozolin caused in a dose-dependent fashion from 2 1 to 14 1-fold increase in the 7-, 6- and 2-hydroxylations of testosterone in liver. Lower increase in extrahepatic tissues ranging from 2 3 to 8 1-fold for testosterone 6-, 16 -, 2- and 2- hydroxylase activity in the kidney or from 2 2 to 5 1-fold for 6-, 16 -, 16 - and 2- hydroxylase activity in the lung were observed. Repeated treatment with this fungicide did not substantially modify the extent and pattern of induction, the liver being the only tissue responsive (up to 7 6-fold increase, 7-hydroxylation) in both male and female. In the kidney (7-, 6-, 16 -, 2-, 7-hydroxylations) and lung (6-, 7-, 6-, 16 -, 16 - and 2- hydroxylations), a typical sex-dependent induction (up to 9 0-fold, 16 -hydroxylation in the lung, female) was achieved. In general, however, vinclozolin has a complex pattern of induction and suppression of CYP-dependent enzymes, as exemplified from the reduced expression of some hydroxylations depending upon dose, sex and organ considered. For example, after a single administration, 16 -hydroxylation was suppressed in liver (up to 78% loss in male, higher dose), whereas 16 -hydroxylation was reduced in kidney up to 50% in both sexes (at the higher dose). Glutathione S-transferase activity, measured as index of post-oxidative reactions, was markedly increased by vinclozolin in the liver (up to 5 2-fold, female) and kidney (up to 3 9-fold, female) but not in the lung. Because both phase I and phase II reactions were enhanced by vinclozolin treatment in liver and kidney, the ratio between activation/detoxification mechanisms was slightly affected. Conversely, this ratio was shifted toward activating mechanisms in the lung, sustaining, in part, the expression of certain type of tumours tissue-dependent. Taken together, these findings seem to indicate the cotoxic, cocarcinogenic and promoting potential of this fungicide.