Bromopropylate: induction of hepatic cytochromes P450 and absence of covalent binding to DNA in mouse liver.
Oral administration of benzilic acid ester-based acaricide bromopropylate at daily doses of 3, 15, 100, and 300 mg/kg body wt to young adult male Tif:MAGf mice for 14 days caused slightly increased liver weights in the high-dose group. A dose-dependent increase of the microsomal cytochrome P450 content was accompanied by elevated ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, and total testosterone hydroxylase activities. When compared with mice treated in parallel with the model compounds for hepatic xenobiotic metabolizing enzyme induction, phenobarbitone, and 3-methylcholanthrene, the enzyme activity changes observed with bromopropylate largely equalled those expressed in phenobarbitone-treated mice. Immunochemical studies with monoclonal antibodies against rat liver cytochrome P450 isoenzymes of the gene families 1A, 2B, 3A, and 4A confirmed that bromopropylate is a phenobarbitone-type inducer in the mouse liver. Titration of liver microsomal suspensions with bromopropylate yielded Type I substrate binding spectra. The specific amplitude was increased 1.5-fold when microsomes from bromopropylate-treated mice (300 mg/kg body wt) were used instead of control microsomes, indicating the induction of cytochromes P450 catalyzing the oxidative metabolism of the test compound. Single oral administration of 300 mg/kg body wt [14C]bromopropylate to male mice, without or following pretreatment for 14 days with 300 mg/kg body wt unlabeled bromopropylate, gave no indication for DNA binding of the test compound in the liver. This excludes a genotoxic potential via covalent DNA modification. The results suggest that, in analogy to phenobarbitone, bromopropylate acts as a tumor promotor rather than a tumor initiator in the mouse liver.
Thomas
H
H
Ciba Crop Protection, Basel, Switzerland.
Sagelsdorff
P
P
Molitor
E
E
Skripsky
T
T
Waechter
F
F
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001189:Aryl Hydrocarbon Hydroxylases; D001561:Benzilates / Q000008:administration & dosage / Q000633:toxicity*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D002458:Cell Fractionation; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D015151:Immunoblotting; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D011897:Random Allocation; D013250:Steroid Hydroxylases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001561:Benzilates; D007306:Insecticides; C038267:isopropyl 4,4'-dibromobenzilate; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D013250:Steroid Hydroxylases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; C022724:testosterone 7-alpha-hydroxylase, hamster