Identification of human and rabbit cytochromes P450 1A2 as major isoforms involved in thiabendazole 5-hydroxylation.
This report characterized one of the major cytochrome P450 isozyme involved in thiabendazole metabolism. This study was undertaken by using both cultured rabbit hepatocytes treated or not with drugs known to specifically induced various cytochromes P450 isoenzymes (i.e., P450 1A1/2 by beta-naphthoflavone, P450 2B4 by phenobarbital, P450 3A6 by rifampicine and P450 4A by clofibrate) and human liver (THLE-5) and bronchial (BEAS-2B) epithelial cells expressing or not the major constitutive human cytochromes P450 (i.e., CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1 or 3A4). Only hepatocytes exposed to beta-naphthoflavone and clofibrate significantly metabolized thiabendazole to 5-hydroxythiabendazole. Extensive biotransformation of this anthelmintic only occurred in human cells expressing CYP1A2. Moreover, experiments performed on rabbit preparations showed good correlations between thiabendazole 5-hydroxylase activity and both ethoxyresorufin and methoxyresorufin O-dealkylase activities. Thus, CYP1A2 is a major isoenzyme involved in thiabendazole 5-hydroxylation.
Coulet
M
M
INRA, Laboratoire de Pharmacologie-Toxicologie, Toulouse, France.
Dacasto
M
M
Eeckhoutte
C
C
Larrieu
G
G
Sutra
J F
JF
Alvinerie
M
M
Macé
K
K
Pfeifer
A M
AM
Galtier
P
P
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000378:metabolism*; D011817:Rabbits; D013045:Species Specificity; D013827:Thiabendazole / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019324:beta-Naphthoflavone; C035151:5-hydroxythiabendazole; D006899:Mixed Function Oxygenases; D019388:Cytochrome P-450 CYP1A2; D002994:Clofibrate; D013827:Thiabendazole