Fukinolic acid derivatives and triterpene glycosides from black cohosh inhibit CYP isozymes, but are not cytotoxic to Hep-G2 cells in vitro.
Black cohosh (Actaea racemosa L. [syn. Cimifuga racemosa L.]) extracts (BCE) are marketed worldwide for the management of menopausal symptoms. However, recently more than 75 cases of hepatotoxicity associated with black cohosh ingestion have been reported. While these cases have not been fully substantiated for causality, the data suggest that herb-drug interactions may be involved rather than a direct hepatotoxic event. This work describes the in vitro inhibition of four CYP450 enzymes (1A2, 2D6, 2C9, 3A4) by black cohosh extracts and identifies the active inhibitory constituents. Ethanol extracts (75 and 80% ethanol) and a 40% isopropanol extract induced a concentration-dependent inhibition of all CYP450 isozyme activities, with median inhibitory concentrations (IC(50)) ranging from 21.9 microg/ml to 65.0 microg/ml. Isolation of the active chemical constituents, showed that the triterpene glycosides were weakly active (IC(50) 25-100 microM), while fukinolic acid and cimicifugic acids A and B strongly inhibited all CYP isozymes (IC(50) 1.8-12.6 microM). None of the extracts inhibited the growth of Hep-G2 cells in concentrations up to 50 microg/ml. These data suggest that BCEs are not directly hepatotoxic, but may have the potential to induce herb-drug interactions, which may in turn explain the rare cases of hepatotoxicity observed in women using multiple medications and dietary supplements, including black cohosh.
Huang
Yue
Y
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St, Chicago, IL 60612, USA.
Jiang
Bei
B
Nuntanakorn
Paiboon
P
Kennelly
Edward J
EJ
Shord
Stacy
S
Lawal
Temitope O
TO
Mahady
G B
GB
D002109:Caffeic Acids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D031885:Cimicifuga; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003603:Cytotoxins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008593:Menopause / Q000187:drug effects / Q000378:metabolism; D010648:Phenylacetates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018517:Plant Roots; D027343:Rhizome; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D002109:Caffeic Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D003603:Cytotoxins; D006027:Glycosides; D007527:Isoenzymes; D010648:Phenylacetates; D010936:Plant Extracts; D014315:Triterpenes; D003577:Cytochrome P-450 Enzyme System; C116090:fukinolic acid
Drugs Aging. 2009;26(1):23-36
19102512
Phytomedicine. 2003 May;10(4):334-42
12809364
Menopause. 2009 Nov-Dec;16(6):1156-66
19609225
J Nat Prod. 2005 Aug;68(8):1266-70
16124775
BMC Pharmacol. 2007 Sep 20;7:11
17880733
Drug Metab Dispos. 1994 Nov-Dec;22(6):909-15
7895609
Evid Based Complement Alternat Med. 2005 Jun;2(2):223-226
15937564
Anal Biochem. 1997 May 15;248(1):188-90
9177742
Phytomedicine. 2004 Feb;11(2-3):98-104
15070158
Toxicol In Vitro. 2005 Mar;19(2):275-87
15649641
Xenobiotica. 1995 Mar;25(3):261-70
7618352
Semin Liver Dis. 2002;22(2):195-206
12016550
Clin Pharmacol Ther. 2005 May;77(5):415-26
15900287
J Nat Prod. 2006 Mar;69(3):314-8
16562825
Maturitas. 2009 Aug 20;63(4):302-14
19586731
Menopause. 2008 Jul-Aug;15(4 Pt 1):628-38
18340277
Mol Nutr Food Res. 2008 Jul;52(7):755-63
18214849
J Clin Pharm Ther. 1999 Oct;24(5):339-46
10583696
J Agric Food Chem. 2003 Sep 10;51(19):5661-70
12952416
J Immunol Methods. 1983 Dec 16;65(1-2):55-63
6606682
Pharmacol Res. 2008 Jul;58(1):8-14
18585461
J Agric Food Chem. 2006 May 3;54(9):3242-53
16637680
J Clin Pharmacol. 2006 Feb;46(2):201-13
16432272
Clin Ther. 2008 Jul;30(7):1206-27
18691982
Expert Opin Drug Metab Toxicol. 2008 Apr;4(4):413-24
18524030
J Nat Prod. 2002 Apr;65(4):601-5
11975513
Ann Intern Med. 2002 Nov 19;137(10):805-13
12435217
J Clin Pharmacol. 2001 Nov;41(11):1149-79
11697750
Pharmacoepidemiol Drug Saf. 2007 Jan;16(1):17-27
16794994
Menopause. 2003 Jul-Aug;10(4):299-313
12851513
J Pharmacol Exp Ther. 1996 Apr;277(1):321-32
8613937
Ann Intern Med. 2006 Dec 19;145(12):869-79
17179056
J Gastroenterol Hepatol. 2000 Oct;15(10):1093-9
11106086
Xenobiotica. 2000 Feb;30(2):141-54
10718122
Treat Endocrinol. 2005;4(3):177-84
15898823
Drugs. 1995 Aug;50(2):222-39
8521756
Cell Mol Life Sci. 2007 Nov;64(21):2848-57
17928951