Carbon monoxide as a guardian against hepatobiliary dysfunction.
Carbon monoxide (CO) generated through the reaction of heme oxygenase (HO) has attracted great interest in regulation of hepatobiliary homeostasis. The gas generated by HO-2 in the hepatic parenchyma can modestly activate soluble guanylate cyclase (sGC) expressed in hepatic stellate cells in a paracrine manner and thereby constitutively relax sinusoids. Kupffer cells express HO-1, the inducible isozyme, even under normal unstimulated conditions and constitutes approximately 30% of the total HO activity in this organ. Upon exposure to a variety of stressors such as cytokines, endotoxin, hypoxia and oxidative stress, the liver induces HO-1 and over-produces CO. The stress-inducible CO has been shown to guarantee ample blood supply during detoxification of heme and thus to play a protective role in the liver. However, molecular mechanisms by which CO serves as a protectant for hepatocytes, the cells expressing little sGC, remain to be solved. Previous observation suggested that CO modulates intracellular calcium mobilization through inhibiting cytochrome P-450 activities and thereby maintain stroke volume of bile canalicular contraction in cultured hepatocytes. CO also stimulates mrp2-dependent excretion of bilirubin-IXalpha and helps heme catabolism. Although a direct molecular target responsible for the latter event remains unknown, such properties of CO could support xenobiotic metabolism through its actions on sinusoidal hemodynamics and hepatobiliary systems.
Suematsu
Makoto
M
Department of Biochemistry and Integrative Medical Biology and Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan. msuem@sc.itc.keiko.ac.jp
Tsukada
Kosuke
K
Tajima
Toshihide
T
Yamamoto
Takehiro
T
Ochiai
Daigo
D
Watanabe
Hiroshi
H
Yoshimura
Yasunori
Y
Goda
Nobuhito
N
D002248:Carbon Monoxide / Q000502:physiology*; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D007728:Kupffer Cells / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000503:physiopathology*; D015398:Signal Transduction
D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2