Shuang Li1, Zhuo-han Hu, Xiao-hui Miao. 1. Department of Infectious Diseases, Changzheng Hospital, the Second Military Medical University, Shanghai 200003, China.
Abstract
OBJECTIVE: To study the effect of HBV on human hepatic cytochrome P450 3A4 (CYP3A4) in patients with chronic HBV infection. METHODS: Liver tissue samples were obtained from 21 patients undergoing hepatic surgery with (n = 10) or without (n = 11) chronic HBV infection and were homogenized, then hepatic microsomes were separated from the homogenate using a differential centrifugation method. The activity of CYP3A4 was determined by HPLC, and the expression of CYP3A4 protein was determined by Western-blotting. RESULTS: The V(max) of CYP3A4 in patients with chronic HBV infection was 493 +/- 297 pmol/min/mg, significantly reduced (P = 0.03) comparing to the normal control group: 741 +/- 189 pmol/min/mg. Western-blotting showed the the CYP3A4 protein expression in patients with chronic HBV infection was 3.04 +/- 1.63, which was significantly lower than that of the normal control group: 5.67 +/- 1.52 (P = 0.003). In contrast, no significant alteration of the K(m) of CYP3A4 was observed between two groups: 0.142 +/- 0.057 micromol/L; 0.121 +/- 0.024 micromol/L (P = 0.103). The enzymatic activity and protein expression of each liver sample had a high correlation. Correlation index was 0.7683 (P < 0.001). CONCLUSION: Chronic HBV infection tends to down-regulate the expression of hepatic CYP3A4 and reduce its activity, but does not affect its structure. When patients with chronic HBV infection are given drugs metabolized by CYP3A4, the drugs' side-effects brought by the variation of their metabolism should be taken into account.
OBJECTIVE: To study the effect of HBV on human hepatic cytochrome P450 3A4 (CYP3A4) in patients with chronic HBV infection. METHODS: Liver tissue samples were obtained from 21 patients undergoing hepatic surgery with (n = 10) or without (n = 11) chronic HBV infection and were homogenized, then hepatic microsomes were separated from the homogenate using a differential centrifugation method. The activity of CYP3A4 was determined by HPLC, and the expression of CYP3A4 protein was determined by Western-blotting. RESULTS: The V(max) of CYP3A4 in patients with chronic HBV infection was 493 +/- 297 pmol/min/mg, significantly reduced (P = 0.03) comparing to the normal control group: 741 +/- 189 pmol/min/mg. Western-blotting showed the the CYP3A4 protein expression in patients with chronic HBV infection was 3.04 +/- 1.63, which was significantly lower than that of the normal control group: 5.67 +/- 1.52 (P = 0.003). In contrast, no significant alteration of the K(m) of CYP3A4 was observed between two groups: 0.142 +/- 0.057 micromol/L; 0.121 +/- 0.024 micromol/L (P = 0.103). The enzymatic activity and protein expression of each liver sample had a high correlation. Correlation index was 0.7683 (P < 0.001). CONCLUSION:Chronic HBV infection tends to down-regulate the expression of hepatic CYP3A4 and reduce its activity, but does not affect its structure. When patients with chronic HBV infection are given drugs metabolized by CYP3A4, the drugs' side-effects brought by the variation of their metabolism should be taken into account.
Authors: Craig D Fisher; Andrew J Lickteig; Lisa M Augustine; James Ranger-Moore; Jonathan P Jackson; Stephen S Ferguson; Nathan J Cherrington Journal: Drug Metab Dispos Date: 2009-08-03 Impact factor: 3.922