Influence of clinicopathological variables on CYP protein expression in human liver.
Drug metabolism is usually impaired in malnourished patients with decompensated cirrhosis, but the separate influence of clinicopathological variables, including nutritional status, on the expression of hepatic cytochrome P450 proteins has not been well characterized. We determined the hepatic content of CYP1A2, CYP2C8/10, CYP2E1 and CYP3A proteins in 71 subjects, 21 with histologically normal livers and 50 with chronic liver disease, and then tested for potential relationships between patient variables and individual CYP proteins by multivariate linear regression analysis. Variables analysed included nutritional status (determined by experienced clinicians), serum albumin and bilirubin concentrations, prothrombin time, the grade of ascites and hepatic encephalopathy, and the Child-Pugh score. Impaired nutrition and cachexia were associated with reductions of CYP2C8/10 levels of approximately 19 and 39%, respectively, relative to cases in which nutrition was replete. Similarly, CYP2E1 protein was reduced by approximately 13 and 26%, according to the apparent severity of nutritional impairment. In contrast, nutritional status did not contribute to variability in expression of CYP1A2 or CYP3A proteins. Of the clinicopathological variables analysed, only serum bilirubin was shown to have an independent influence on CYP protein content. Thus, elevated serum bilirubin concentrations were associated with significant declines in the contents of CYP1A2 and CYP2C8/10 but not CYP3A or CYP2E1. The mechanisms for the effects of nutritional status and serum bilirubin concentration on the levels of CYP proteins are unclear, but could be mediated by factors such as cytokines, dietary composition and alterations in the level of serum bile acids. Knowledge of the influence of clinicopathological factors and nutritional status on CYP expression should lead to more rational drug prescribing in patients with hepatic disease.
George
J
J
Department of Gastroenterology and Hepatology, University of Sydney at Westmead Hospital, New South Wales, Australia.
Byth
K
K
Farrell
G C
GC
D001663:Bilirubin / Q000097:blood; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005260:Female; D006501:Hepatic Encephalopathy / Q000201:enzymology; D006801:Humans; D016014:Linear Models; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009752:Nutritional Status; D011517:Prothrombin Time; D012709:Serum Albumin / Q000378:metabolism
D012709:Serum Albumin; D003577:Cytochrome P-450 Enzyme System; D001663:Bilirubin