Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice.
OBJECTIVE
We showed previously that a Kampo (Chinese/Japanese herbal) medicine, Inchin-ko-to (ICKT), inhibits hepatocyte apoptosis induced by transforming growth factor beta1 in vitro. The present study investigated whether ICKT or its ingredients inhibit Fas-mediated liver apoptosis in vivo.


METHODS
Acute liver injury was induced by an intravenous injection of anti-Fas antibody, Jo2. The effects of ICKT and its ingredients on lethality, histology, apoptotic index, serum transaminase levels, caspase activation, mitochondrial membrane potential (Deltapsi(m)), and mitochondrial permeability transition (MPT) were analyzed. Apoptosis in mouse hepatocytes in vitro was also evaluated.


RESULTS
Pretreatment with ICKT rescued 75% of Jo2-treated mice and markedly suppressed liver apoptosis/injury. Genipin, an intestinal bacterial metabolite of geniposide that is a major ingredient of ICKT, was found to be an active principle of ICKT. Genipin also suppressed in vitro Fas-mediated apoptosis in primary-cultured murine hepatocytes. Activation of caspase 3 and 8 in the liver homogenate and rapid reduction of triangle uppsi(m) of hepatocytes isolated from Jo2-treated mice were inhibited by genipin preadministration. The resistance to Ca(2+)-induced MPT was enhanced in liver mitochondria of genipin-treated mice.


CONCLUSIONS
These results suggest that the antiapoptotic activity of genipin via the interference with MPT is a possible mechanism for therapeutic effects of ICKT.
Yamamoto
M
M
Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura & Co., Ibaraki, Japan. hirokomo@po.iijnet.or.jp
Miura
N
N
Ohtake
N
N
Amagaya
S
S
Ishige
A
A
Sasaki
H
H
Komatsu
Y
Y
Fukuda
K
K
Ito
T
T
Terasawa
K
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001219:Aspartate Aminotransferases / Q000097:blood; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D005260:Female; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D057889:Iridoid Glycosides; D039823:Iridoids; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology; D010539:Permeability; D010946:Plants, Medicinal; D011714:Pyrans / Q000494:pharmacology*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology*
D002756:Cholagogues and Choleretics; D057889:Iridoid Glycosides; D039823:Iridoids; D011714:Pyrans; D019014:fas Receptor; C007835:geniposide; D019695:Glycyrrhizic Acid; D014580:Ursodeoxycholic Acid; C007834:genipin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase