Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases.
OBJECTIVE
To determine whether parenchymal cells or hepatic cytochrome P450 protein was changed in chronic liver diseases, and to compare the difference of CYP3A4 enzyme and its gene expression between patients with hepatic cirrhosis and obstructive jaundice, and to investigate the pharmacologic significance behind this difference.


METHODS
Liver samples were obtained from patients undergoing hepatic surgery with hepatic cirrhosis (n=6) and obstructive jaundice (n=6) and hepatic angeioma (controls, n=6). CYP3A4 activity and protein were determined by Nash and western blotting using specific polychonal antibody, respectively. Total hepatic RNA was extracted and CYP3A4cDNA probe was prepared according the method of random primer marking, and difference of cyp3a4 expression was compared among those patients by Northern blotting.


RESULTS
Compared to control group, the CYP3A4 activity and protein in liver tissue among patients with cirrhosis were evidently reduced. (P<0.01) Northern blot showed the same change in its mRNA levels. In contrast, the isoenzyme and its gene expression were not changed among patients with obstructive jaundice.


CONCLUSIONS
Hepatic levels of P450s and its CYP3A4 isoform activity were selectively changed in different chronic liver diseases. CYP3A4 isoenzyme and its activity declined among patients with hepatic cirrhosis as expression of cyp3a4 gene was significantly reduced. Liver's ability to eliminate many clinical therapeutic drug substrates would decline consequently. These findings may have practical implications for the use of drugs in patients with cirrhosis and emphasize the need to understand the metabolic fate of therapeutic compounds. Elucidation of the reasons for these different changes in hepatic CYP3A4 may provide insight into more fundamental aspects and mechanisms of imparied liver function.
Yang
Li-Qun
LQ
Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200438, China. liqunyang@yahoo.com
Li
Shen-Jing
SJ
Cao
Yun-Fei
YF
Man
Xiao-Bo
XB
Yu
Wei-Feng
WF
Wang
Hong-Yang
HY
Wu
Meng-Chao
MC
D000328:Adult; D002908:Chronic Disease; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000503:physiopathology*; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000378:metabolism
D020033:Protein Isoforms; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human