Effects of benzothiazole on the xenobiotic metabolizing enzymes and metabolism of acetaminophen.
Benzothiazole (BT) is present in tobacco smoke and widely used for industrial and pharmaceutical purposes. In this study we have investigated the influence of BT on the activities of hepatic cytochrome P450 monooxygenases (P450s) and UDP-glucuronyltransferase (UDP-GT), sulphotransferase and glutathione-S-transferase (GST) in male Sprague-Dawley rats. We also examined if BT would change the metabolism and toxification of acetaminophen (AA) through modulation of metabolizing enzymes. Benzothiazole (1 mmol kg(-1), p.o., 5 days) markedly increased the enzyme activities of P4501A1, 1A2, 2B1, 3A4, 2E1, UDP-GT and GST in liver. Pretreatment with BT significantly decreased the amount of total AA recovered in bile to 68.5% of controls, mainly as a consequence of reduced AA-glucuronide conjugate (35.3% of controls), whereas the AA-glutathione conjugate (AA-GS) was augmented to 1.6-fold. After pretreatment with BT, potentiation of the hepatotoxicity by AA (400 mg kg(-1), i.p., 24 h) was observed by measuring serum alanine aminotransferase activities in ICR mice. These results indicate that: BT is a potent inducer of P450s and phase II metabolizing enzymes; and the increase of AA-GS conjugate and aggravation of AA hepatotoxicity by BT may be related to induction of P450s.
Seo
K W
KW
Toxicology Department, National Institute of Toxicological Research, Korea Food and Drug Administration, 5 Nokbundong, Eunpyunggu, Seoul 122-020, Korea.
Park
M
M
Kim
J G
JG
Kim
T W
TW
Kim
H J
HJ
D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D015239:Arylsulfotransferase; D052160:Benzothiazoles; D001646:Bile / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism*; D008658:Inactivation, Metabolic; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015238:Sulfotransferases / Q000096:biosynthesis / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
D018712:Analgesics, Non-Narcotic; D052160:Benzothiazoles; D013844:Thiazoles; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C005465:benzothiazole