title: Severely Impaired and Dysregulated Cytochrome P450 Expression and Activities in Hepatocellular Carcinoma: Implications for Personalized Treatment in Patients.
abstract: This study aims to systematically determine the activities and expressions of cytochrome P450s (CYP) in hepatocellular carcinoma (HCC) patients to support their optimal use in personalized treatment of HCC. Activities of seven major drug-metabolizing CYP enzymes (CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, and 3A4) were determined in tumors and pericarcinomatous tissues harvested from 26 patients with hepatitis B virus-positive HCC using probe substrates. Protein and mRNA levels of these CYPs were also measured using isotope label-free LC/MS-MS method and real-time PCR, respectively. Maximal metabolic velocity (Vmax) of CYP probe substrates was decreased by 2.5- to 30-fold in tumor microsomes, accompanied by a corresponding decrease in their protein and mRNA expression levels. However, Km values and turnover numbers of substrates in tumor microsomes were not changed. High correlations between activities and CYP protein levels were also observed, but the correlation between activities and mRNA levels was often poor. There was a major decrease in the degree of correlation in CYP expression in tumor tissues, suggesting that CYP expression levels are greatly disrupted by the tumorigenic process. Our unprecedented systemic study of the effects of HCC on CYPs demonstrated that activities of CYPs were seriously impaired and their expression patterns were severely altered by HCC. We proposed that determination of the CYP protein expression profile by LC/MS-MS in each patient is a promising approach that can be clinically used for individualized treatment of HCC.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Tongmeng
authors.initials: T
authors.lastname: Yan
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Xie
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Peng
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Fuyuan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas. liuzq@gzucm.edu.cn mhu@uh.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. liuzq@gzucm.edu.cn mhu@uh.edu.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003374:Coumarins / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000145:classification; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006515:Hepatitis B virus / Q000472:pathogenicity; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D057285:Precision Medicine; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D003374:Coumarins; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin