Strychnine and brucine as the potent inducers of drug metabolizing enzymes in rat liver: different profiles from phenobarbital on the induction of cytochrome P450 and UDP-glucuronosyltransferase.
The inducing activities of two alkaloids, strychnine and brucine, on the hepatic drug metabolizing enzymes were studied in rats. Administration of strychnine in the drinking water to rats significantly increased the hepatic microsomal activities of benzphetamine N-demethylation, strychnine 2-hydroxylation and testosterone hydroxylations at positions 16 alpha and 16 beta. These results together with that of immunostaining of microsomal proteins revealed that strychnine is a potent inducer of CYP2B1 and 2B2. The comparable induction of CYP2B1/2 was observed by brucine treatment with less toxic effect. Although this inducer increased CYP2B cytochrome P450s (P450s) to the maximum levels after 4 consecutive days of administration, the maximal increase by strychnine was attained after 3 days of administration. Immunoblotting experiment suggested that significant proteolysis of CYP2B1 occurs during treatment by strychnine and brucine. These alkaloids exhibited no ability to induce the activities of testosterone hydroxylations at positions 2 alpha, 6 beta and 7 alpha, benzo[a]pyrene 3-hydroxylation and aniline hydroxylation. In addition to the CYP2B P450, strychnine and brucine induced glutathione S-transferase toward 1-chloro-2,4-dinitrobenzene and UDP-glucuronosyltransferase toward 4-nitrophenol. On the other hand, the glucuronidations of 4-hydroxybiphenyl and morphine were not enhanced by alkaloid treatments. These results indicated that strychnine and brucine cause phenobarbital-like induction of the P450 enzyme, but show a different profile from phenobarbital in the induction of UDP-glucuronosyltransferase.
Fujisaki
H
H
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Mise
M
M
Ishii
Y
Y
Yamada
H
H
Oguri
K
K
D000818:Animals; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D005982:Glutathione Transferase / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010088:Oxidoreductases / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013331:Strychnine / Q000494:pharmacology* / Q000633:toxicity
D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D013331:Strychnine; D010634:Phenobarbital