CYP superfamily perturbation by diflubenzuron or acephate in different tissues of CD1 mice.
This work aimed to investigate whether the insecticide acephate (125 or 250 mg/kg b.w.) or diflubenzuron (752 or 1075 mg/kg b.w.), two of the most widely used pesticides worldwide, impairs CYP-linked murine metabolism in liver, kidney and lung microsomes after repeated (daily, for three consecutive days) i.p. administration. The regio- and stereo-selective hydroxylation of testosterone was used as multibiomarker of different CYP isoforms. Both gender and tissue specific effects were observed. Lung was the most responsive tissue to induction by lower diflubenzuron dose, as exemplified by the marked increase of testosterone 7alpha-hydroxylation (CYP2A) (up to 13-fold) in males. Higher dose produced a generalized inactivation. At the lower dose acephate induced 6beta- (CYP3A1/2, liver) as well as 2beta- (CYP2B1/2, kidney) hydroxylase activities ( approximately 5 and approximately 4-fold increase, respectively) in males. In females, a marked suppression of the various hydroxylations was observed. At 250 mg/kg of acephate, animals did not survive. Induction of the most affected isoforms was sustained by immunoblotting analysis. Corresponding human CYP modulations might disrupt normal physiological functions related to these enzymes. Furthermore, the co-mutagenic and promoting potential of these pesticides, phenomena linked to CYP upregulation (e.g. increased bioactivation of ubiquitous pollutants and generation of oxygen free radicals) are of concern for a more complete definition of their overall toxicological potential.
Sapone
A
A
Department of Pharmacology, Molecular Toxicology Unit, Alma-Mater Studiorum, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy. andrea.sapone@unio.it
Pozzetti
L
L
Canistro
D
D
Broccoli
M
M
Bronzetti
G
G
Potenza
G
G
Affatato
A
A
Biagi
G L
GL
Cantelli-Forti
G
G
Paolini
M
M
D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism*; D004132:Diflubenzuron / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D007274:Injections, Intraperitoneal; D007306:Insecticides / Q000633:toxicity*; D007527:Isoenzymes; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009928:Organ Specificity; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D063088:Phosphoramides; D012737:Sex Factors; D013739:Testosterone / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D036401:Toxicity Tests, Chronic
D007306:Insecticides; D007527:Isoenzymes; D009946:Organothiophosphorus Compounds; D063088:Phosphoramides; D013739:Testosterone; C001969:acephate; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D004132:Diflubenzuron