title: Molecular non-genetic biomarkers of effect related to acephate cocarcinogenesis: sex- and tissue-dependent induction or suppression of murine CYPs.
abstract: The aim of this work was to study the ability of the organophosphate insecticide acephate to alter some biochemical markers of effect related non-genetic cocarcinogenesis. For this purpose, selective CYP-dependent reactions have been examined in liver, kidney and lung microsomes of male and female Swiss albino CD1-mice treated (i.p.) with a 125 or 250 mg/kg b.w. dose of this pesticide. High specific substrates were used as a probe of various isozymes, such as CYP 1A1, 1A2, 2B1, 2E1 and 3A. Maked organ- and sex-related differences in either inducive or suppressive response by acephate depict a complex pattern of CYP modulation with the kidney being more responsive to 3A induction (up to 6.9-fold increase, male) and the lung to 2B1 suppression (up to 70% loss, mainly female). In the liver, a 2.7-fold increase in the 3A-like activity, probed by the O-demethylation of aminopyrine, in the O-deethylation of phenacetin (1.8-fold increase, 1A2), as well as in the hydroxylation of p-nitrophenol (1.6-fold increase, 2E1) was observed in male animals at a lower dose. In contrast, a marked reduction of CYP 1A1-mediated ethoxyresorfin O-deethylase activity ranging from 43% (lower dose) to 44% loss (higher dose) in female and male mice, respectively, and of CYP 2B1-mediated pentoxyresorufin O-dealkylase (3% loss, female) was achieved. In the kidney, an increase in the 'mixed' ethoxycoumarin O-deethylase (up to 2-fold) as well as in the 2B1-like activity (up to 2.8-fold) was also recorded in males at 250 mg/kg. Once again, in the lung, a different behaviour on 3A isoforms between female (approximately 2-fold increase) and male (44% loss) was seen at a lower dose. The specificity of CYP changes was corroborated by means of Western immunoblotting analysis using rabbit polyclonal antibodies, anti-CYP 3A1/2 and 2E1. Taken together, these data indicate a possible toxic/cotoxic, cocarcinogenic and promoting potential of acephate.
authors.affiliation: Department of Pharmacology, University of Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Paolini
authors.forename: L
authors.initials: L
authors.lastname: Pozzetti
authors.forename: A
authors.initials: A
authors.lastname: Sapone
authors.forename: R
authors.initials: R
authors.lastname: Mesirca
authors.forename: P
authors.initials: P
authors.lastname: Perocco
authors.forename: M
authors.initials: M
authors.lastname: Mazzullo
authors.forename: G
authors.initials: G
authors.lastname: Cantelli-Forti
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D003043:Cocarcinogenesis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007306:Insecticides / 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; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D063088:Phosphoramides; D012737:Sex Factors
chemical_list: D007306:Insecticides; D009946:Organothiophosphorus Compounds; D063088:Phosphoramides; C001969:acephate; D003577:Cytochrome P-450 Enzyme System