Characterization of nuciferine metabolism by P450 enzymes and uridine diphosphate glucuronosyltransferases in liver microsomes from humans and animals.
OBJECTIVE
to characterize the metabolism of nuciferine by P450 enzymes and uridine diphosphate glucuronosyltransferase (UGT) in liver microsomes from humans and several other animals including rats, mice, dogs, rabbits and monkeys.


METHODS
nuciferine was incubated with both human and animal liver microsomal fractions containing P450 or UGT reaction components. Ultra performance liquid chromatography coupled with mass spectrometry was used to separate and identify nuciferine metabolites. Chemical inhibition was used to identify the involved isozymes. Species difference of nuciferine metabolism in human and various animals were investigated in the liver microsomal incubation system.


RESULTS
among the nuciferine metabolites detected and identified, seven were catalyzed by P450 and one by UGT. Ketoconazole inhibited the formation of M292, M294 and M312. Furafylline, 8-methoxypsoralen and quercetin inhibited the formation of M282. Hecogenin showed a significant inhibitory effect on nuciferine glucuronidation. While the P450-catalyzed metabolites showed no species differences, the glucuronidation product was only detected in microsomes from humans and rabbits.


CONCLUSIONS
the isozymes UGT 1A4, CYP 3A4, 1A2, 2A6 and 2C8 participated in the hepatic metabolism of nuciferine. Based on the observed species-specific hepatic metabolism of nuciferine, rats, mice, dogs and even monkeys are not suitable models for the pharmacokinetics of nuciferine in humans.
Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
Yan-liu
YL
LU
Yu-qi
YQ
HE
Miao
M
WANG
Li
L
ZHANG
Li
L
YANG
Zheng-tao
ZT
WANG
Guang
G
JI
D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D014453:Glucuronosyltransferase / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D014530:Uridine Diphosphate / Q000378:metabolism*
D001060:Aporphines; D007527:Isoenzymes; D014530:Uridine Diphosphate; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C008692:nuciferine