Differential induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene in mice and Chinese hamsters.
Induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene (BHT) was studied in the male ddY mouse and Chinese hamster. In mice given 0.05 and 0.15% BHT in the diet for 14 days cytochrome P-450 contents and the activities of uridine diphosphate-glucuronyl transferase (UDP-GT) and pentoxyresorufin O-dealkylase were markedly increased, while in those fed 0.15% BHT testosterone 6 alpha-, 16 alpha- and 16 beta-hydroxylases were greatly increased, which indicated induction of cytochrome P-450 isozymes of the CYP2B family. Western blot analysis also showed an increased level of the isozyme immunorelated to rat CYP2B2 by BHT feeding. The activities of aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase (ECOD), erythromycin N-demethylase and glutathione S-transferase (GST) remained unchanged. In Chinese hamsters given 0.05 and 0.15% BHT in the diet for 14 days activities of ECOD and GST were induced, but cytochrome P-450 contents and the activities of other enzymes were unaffected. Testosterone 15 alpha-hydroxylase was induced in hamsters fed 0.15% BHT. These findings suggested that BHT administration in the hamster induced CYP2A2-type isozyme, which was confirmed by Western blot analysis. BHT treatment enhanced activation of benzo[a] pyrene (B[a]P) as determined by the mutagenicity test, especially in Chinese hamsters. The results suggest that BHT treatment induces specific isozymes of drug-metabolizing enzymes and might modify the expression of toxicities of other chemicals.
Sun
B
B
Department of Pharmaceutical Sciences, National Institute of Public Health, Tokyo, Japan.
Fukuhara
M
M
Kinoshita
T
T
Kimura
M
M
Ushio
F
F
D015660:7-Alkoxycoumarin O-Dealkylase / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001564:Benzo(a)pyrene / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002084:Butylated Hydroxytoluene / Q000494:pharmacology*; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D005520:Food Preservatives / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000187:drug effects; D007527:Isoenzymes / Q000096:biosynthesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D009152:Mutagenicity Tests; D009929:Organ Size / Q000187:drug effects; D012269:Ribosomal Proteins / Q000737:chemistry; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000187:drug effects; D015262:Xenobiotics / Q000633:toxicity
D005520:Food Preservatives; D007527:Isoenzymes; D012269:Ribosomal Proteins; D015262:Xenobiotics; D002084:Butylated Hydroxytoluene; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster; D005982:Glutathione Transferase