Albendazole sulfonation by rat liver cytochrome P-450c.
The metabolism of albendazole (ABZ) was studied in perfused livers from control and ABZ-treated rats (10.6 mg/kg, per os, each day for 10 days). In the perfusion fluid, the concentration of ABZ-sulfoxide (SO-ABZ) remained unchanged in treated, as compared to control animals, whereas ABZ-sulfone (SO2-ABZ) was increased in treated animals. In bile, only SO-ABZ was present. The transformation kinetics of SO-ABZ to SO2-ABZ in microsomes from rats treated with ABZ, 3-methylcholanthrene, Aroclor and isosafrole were biphasic. This suggests that enzyme activity was a consequence of two enzyme systems, one characterized by low affinity and high capacity, the other by high affinity and low capacity, the latter could be induced by 3-methylcholanthrene, ABZ, Aroclor and isosafrole. Cytochrome P-450c was induced potently in vivo by ABZ as proven by increased monooxygenase (7-ethoxyresorufin and 7-ethoxycoumarin-O-deethylase) activities and by Elisa test (a 5-fold increase in hemoprotein concentration was observed). Purified and reconstituted cytochrome P-450c from 3-methylcholanthrene or ABZ-treated rat liver were able to produce SO2-ABZ (2.01 and 1.70 nmol/mg/15 min, respectively, whereas cytochrome P-450b produced 10 times less SO2-ABZ). Immunological assays, as well as activity measurements showed a relationship between cytochrome P-450c-3-methylcholanthrene and cytochrome P-450c-ABZ. We conclude that induction of cytochrome P-450c by ABZ is the probable explanation for the enhanced formation of SO2-ABZ in vivo.
Souhaili-El Amri
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Centre du Médicament, U.A. Centre National de la Recherche Scientifique, Faculté des Sciences Pharmaceutiques et Biologiques, Nancy, France.
Mothe
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Totis
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Masson
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Batt
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Delatour
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Siest
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D015766:Albendazole / Q000031:analogs & derivatives; D000818:Animals; D000871:Anthelmintics / Q000378:metabolism*; D001140:Aroclors / Q000494:pharmacology; D001562:Benzimidazoles / Q000032:analysis / Q000378:metabolism*; D001711:Biotransformation; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012451:Safrole / Q000494:pharmacology
D000871:Anthelmintics; D001140:Aroclors; D001562:Benzimidazoles; D020111:Chlorodiphenyl (54% Chlorine); C027187:albendazole sulfone; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D015766:Albendazole; C027186:albendazole sulfoxide; D012451:Safrole; C015959:isosafrole