INFLUENCE OF CLINICOPATHOLOGICAL VARIABLES ON CYP PROTEIN EXPRESSION IN HUMAN LIVER

Drug metabolism is usually impaired in malnourished patients with deco mpensated cirrhosis, but the separate influence of clinicopathological variables, including nutritional status, on the expression of hepatic cytochrome P450 proteins has nor been well characterized. We determin ed the hepatic content of CYP1A2, CYP2C8/10, CYP2E1 and CYP3A proteins in 71 subjects, 21 with histologically normal livers and 50 with chro nic 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 (d etermined by experienced clinicians), serum albumin and bilirubin conc entrations, prothrombin time, the grade of ascites and hepatic encepha lopathy, and the Child-Pugh score. Impaired nutrition and cachexia wer e associated with reductions of CYP2C8/10 levels of approximately 19 a nd 39%, respectively, relative to cases in which nutrition was replete . Similarly, CYP2E1 protein was reduced by approximately 13 and 26%, a ccording to the apparent severity of nutritional impairment. In contra st, nutritional status did not contribute to variability in expression of CYP1A2 or CYP3A proteins. Of the clinicopathological variables ana lysed, 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 a nd CYP2C8/10 but not CYP3A or CYP2E1. The mechanisms for the effects o f nutritional status and serum bilirubin concentration on the levels o f CYP proteins are unclear, but could be mediated by factors such as c ytokines, dietary composition and alterations in the level of serum bi le acids. Knowledge of the influence of clinicopathological factors an d nutritional status on CYP expression should lead to more rational dr ug prescribing in patients with hepatic disease.