Distinct role of bilobalide and ginkgolide A in the modulation of rat CYP2B1 and CYP3A23 gene expression by Ginkgo biloba extract in cultured hepatocytes.
In the present study, primary cultures of rat hepatocytes were treated for 48 h with one of several extracts of Ginkgo biloba (10, 100, or 1000 microg/ml). Maximal increase in CYP2B1 and CYP3A23 mRNA levels was obtained at 100 microg/ml. This concentration of G. biloba extract also increased CYP3A2 and CYP3A18 mRNA expression in addition to CYP2B-mediated 7-benzyloxyresorufin O-dealkylation (BROD) and CYP3A-mediated testosterone 6beta-hydroxylation. In other experiments, cultured hepatocytes were treated for 48 h with bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, kaempferol, quercetin, isorhamnetin, or a flavonol diglycoside at a concentration that represented the level present in a 100 microg/ml concentration of an extract. Only bilobalide (2.8 microg/ml) increased CYP2B1 mRNA expression, and the -fold increase (7.9 +/- 0.5; mean +/- S.E.M.) was similar to that (8.3 +/- 1.7) by the extract. By comparison, only ginkgolide A (1.1 microg/ml) increased CYP3A23 mRNA expression, but the extent (2.6 +/- 0.5-fold) was less than the 5.3 +/- 1.7-fold increase by the extract. A greater concentration (5 microg/ml) of ginkgolide A was required to elevate CYP3A2 and CYP3A18 mRNA expression. Over the range of 1 to 5 microg/ml, bilobalide increased CYP2B1 mRNA and BROD, but not CYP3A23 mRNA or testosterone 6beta-hydroxylation, whereas ginkgolide A increased CYP3A23 mRNA and testosterone 6beta-hydroxylation, but not CYP2B1 mRNA or BROD. Overall, our novel results indicate a distinct role of bilobalide and ginkgolide A in the modulation of CYP2B1 and CYP3A23 gene expression and enzyme activities by G. biloba extract in primary cultures of rat hepatocytes.
Chang
Thomas K H
TK
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada. tchang@interchange.ubc.ca
Chen
Jie
J
Teng
Xiao Wei
XW
D000818:Animals; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020441:Ginkgo biloba / Q000737:chemistry*; D046934:Ginkgolides; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism
D003517:Cyclopentanes; D004224:Diterpenes; D005663:Furans; D046934:Ginkgolides; D007783:Lactones; D010936:Plant Extracts; D012333:RNA, Messenger; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; C073710:bilobalide; C477042:ginkgolide A