Nicotine metabolism in liver microsomes from rats with acute hepatitis or cirrhosis.
Nicotine exerts a number of physiological effects. Nicotine is absorbed through the lungs with smoking and is rapidly metabolized in humans. Although it is mainly metabolized in the liver, the effects of liver injuries on nicotine metabolism are not clear. The purpose of this study was to clarify the effects of liver injuries on nicotine metabolism. Rats were treated with D-galactosamine (GalN) or thioacetamide (TA), to induce acute hepatitis or liver cirrhosis, respectively. Serum transaminase levels were significantly elevated in model rats with both types of liver injury. Cytochrome P450 (CYP) and cytochrome b5 contents in liver microsomes were decreased significantly in TA-treated cirrhotic rats but not in GalN-treated hepatitic rats. The major metabolic pathways of nicotine, i.e. cotinine formation catalyzed by CYP and nicotine-1'-N-oxide formation catalyzed by flavin-containing monooxygenase, were investigated in these rat liver microsomes. Formation of cotinine and nicotine-1'-N-oxide from nicotine was not changed in GalN-treated hepatitic rats, in comparison with the controls, but was significantly decreased in TA-treated cirrhotic rats. By immunoblotting, decreases in CYP1A2, CYP2B2, CYP2C, and CYP2E1 protein were recognized in liver microsomes from TA-treated cirrhotic rats. It was also shown that the maximal velocity values for nicotine-1'-N-oxide formation in TA-treated cirrhotic rats were significantly decreased, compared with the controls. These results suggested that the reduction of nicotine metabolism in cirrhosis was due to decreases in CYP and flavin-containing monooxygenase protein expression levels.
Nakajima
M
M
Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Iwata
K
K
Yamamoto
T
T
Funae
Y
Y
Yoshida
T
T
Kuroiwa
Y
Y
D000208:Acute Disease; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D005688:Galactosamine / Q000009:adverse effects; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000378:metabolism*; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000009:adverse effects; D013997:Time Factors; D000637:Transaminases / Q000097:blood
D003497:Cyclic N-Oxides; D013853:Thioacetamide; D009538:Nicotine; D005688:Galactosamine; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase; D000637:Transaminases