MOLECULAR NONGENETIC BIOMARKERS RELATED TO FENARIMOL COCARCINOGENESIS- ORGAN-SPECIFIC AND SEX-SPECIFIC CYP INDUCTION IN RAT

Selective biochemical markers of effect have been used to evaluate som e non-genotoxic cocarcinogenic properties of Fenarimol. Several CYP-de pendent reactions have been monitored in liver, kidney and lung micros omes of male and female Sprague-Dawley rats treated (i.p.) with 200 or 400 mg/kg body wt dose of this pesticide. Highly specific substrates were used as probes of various isoforms, such as CYP1A1, 1A2, 2B1, 2E1 and 3A. A complex pattern of CYP induction, including organ- and sex- related differences in the inductive response by Fenarimol, has been r ecorded in this investigation, the kidney (mainly male) being more res ponsive when compared to other tissues. A 6.6-fold increase in the 2B1 -like activity, probed by dealkylation of pentoxyresorufin was observe d in the liver at a higher dose. On the contrary, a marked induction o f CYP1A1 mediated ethoxyresorufin O-deethylase activity, ranging from 20- to 35-fold in female and male, respectively, was observed in the k idney at a lower dose tested. In the lung, at a higher dose, the p-nit rophenol hydroxylase activity (2E1) was enhanced up to 3.5-fold in mal e animals, whereas the 3A-like activity, probed by the N-demethylation of aminopyrine, was induced up to 2.6-fold in females, A weak, althou gh significant reduction of CYP2B1 isoforms in lung was also recorded. Taken together, these data corroborated by means of Western immunoblo tting analysis (using rabbit polyclonal antibodies anti-CYP 2B1/2, 1A1 , 2E1 and 3A1/2) indicate a possible cotoxic, comutagenic/cocancerogen ic and promoting potential of this fungicide.