Taurochenodeoxycholic acid induced biphasic hepatotoxicity in isolated perfused rat liver: roles of Ca2+ and calpain.
OBJECTIVE
We examined taurochenodeoxycholic acid-induced hepatotoxicity with reference to Ca2+ and calpain involvement, intracellular bile acid content, and zone specificity in isolated perfused rat liver.


METHODS
Taurochenodeoxycholic acid or chenodeoxycholic acid was infused into the portal vein and lactate dehydrogenase release, a marker of hepatocyte injury, in the effluent and bile acid output were measured in the presence and absence of either nickel, a membranous Ca2+ channel blocker, or calpain inhibitor in isolated perfused rat liver.


RESULTS
Taurochenodeoxycholic acid induced a significant and transient increase (first peak; 4 min) and subsequent time- and dose-dependent elevation in lactate dehydrogenase release which was proportional to accumulated bile acids in the liver. Although the first peak was significantly suppressed by pretreatment with nickel, the subsequent release was not reduced. Lactate dehydrogenase release at 15, 20, and 25 min was significantly suppressed by the calpain inhibitor. Numbers of damaged hepatocytes stained with trypan blue were significantly increased in the periportal region (zone 1) compared with the pericentral region (zone 3) and these cells were consistently stained with anti-calpain antibody.


CONCLUSIONS
Taurochenodeoxycholic acid causes both transient damage and subsequent increasing hepatotoxicity which are respectively dependent on Ca2+ influx via membranous Ca2+ channels and calpain, with the periportal region being more susceptible.
Hasegawa
Chihiro
C
First Department of Internal Medicine, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya Aichi, 467-8601, Japan.
Yamada
Tamaki
T
Ohara
Hirotaka
H
Nakazawa
Takahiro
T
Sano
Hitoshi
H
Ando
Hakuji
H
Kunimatsu
Mitoshi
M
Ozaki
Yasuhiko
Y
Takahashi
Satoru
S
Nomura
Tomoyuki
T
Joh
Takashi
T
Itoh
Makoto
M
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002118:Calcium / Q000502:physiology*; D002154:Calpain / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000009:adverse effects*
D001647:Bile Acids and Salts; D013655:Taurochenodeoxycholic Acid; D007770:L-Lactate Dehydrogenase; D002154:Calpain; D002118:Calcium