Molecular non-genetic biomarkers related to Fenarimol cocarcinogenesis: organ- and sex-specific CYP induction in rat.
Selective biochemical markers of effect have been used to evaluate some non-genotoxic cocarcinogenic properties of Fenarimol. Several CYP-dependent reactions have been monitored in liver, kidney and lung microsomes of male and female Sprague-Dawely 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 recorded in this investigation, the kidney (mainly male) being more responsive when compared to other tissues. A 6.6-fold increase in the 2B1-like activity, probed by dealkylation of pentoxyresorufin was observed in the liver at a higher dose. On the contrary, a marked induction of CYP1A1 mediated ethoxyresorufin O-deethylase activity, ranging from 20- to 35-fold in female and male, respectively, was observed in the kidney at a lower dose tested. In the lung, at a higher dose, the p-nitrophenol hydroxylase activity (2E1) was enhanced up to 3.5-fold in male animals, whereas the 3A-like activity, probed by the N-demethylation of aminopyrine, was induced up to 2.6-fold in females. A weak, although significant reduction of CYP2B1 isoforms in lung was also recorded. Taken together, these data corroborated by means of Western immunoblotting analysis (using rabbit polyclonal antibodies anti-CYP 2B1/2, 1A1, 2E1, and 3A1/2) indicate a possible cotoxic, comutagenic cocancerogenic and promoting potential of this fungicide.
Paolini
M
M
Department of Pharmacology, University of Bologna, Italy.
Mesirca
R
R
Pozzetti
L
L
Sapone
A
A
Cantelli-Forti
G
G
D015660:7-Alkoxycoumarin O-Dealkylase / Q000096:biosynthesis / Q000187:drug effects; D000633:Aminopyrine N-Demethylase / Q000096:biosynthesis / Q000187:drug effects; D000818:Animals; D003043:Cocarcinogenesis; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis / Q000187:drug effects; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D005659:Fungicides, Industrial; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D015660:7-Alkoxycoumarin O-Dealkylase; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D000633:Aminopyrine N-Demethylase; C033789:fenarimol