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 realtime PCR, respectively. Maximal metabolic velocity (V max ) 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, K m 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.

Assessment of Gold Nanoparticles-Inhibited Cytochrome P450 3A4 Activity and Molecular Mechanisms Underlying Its Cellular Toxicity in Human Hepatocellular Carcinoma Cell Line C3A

“…Recent studies reported that the 40 nm BPEI-AuNP inhibited gene expression of CYP1A2, CYP2C9, and CYP3A4 in human hepatocytes; ESD in HUVEC; and CYP1A1 in HPTC [ 7 – 9 ]. Epidemiology study demonstrated that CYP enzymes in liver tissue of HCC patient were substantially inhibited by the tumorigenic process at the molecular and the functional level [ 41 ].…”

Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma

“…Yan et al investigated the activity of seven CYPs in tumors obtained from 26 patients with HCC [13]. The results showed that activity of these seven CYP isoforms was decreased in tumor human liver microsomes (HLMs) relative to those in pericarcinomatous HLMs and control HLMs.…”

Comprehensive Analysis of the Expression and Prognosis of 12 Cytochrome P450s in Human Hepatocellular Carcinoma from the Perspective of Network Pharmacology

“…The expression level of CYP1A2 is markedly decreased in HCC [6]. Hence, the determination of CYP protein expression pro le is useful for personalized HCC treatment [4]. The results of the present study showed that the expression level of CYP1A2 dramatically decreased in HCC, and its low expression level was correlated with individual cancer stages and tumor grades.…”

“…Accumulating evidence shows that CYPs are concerned not only with biotransformation of carcinogens and antineoplastic drugs but also serve as vital therapeutic targets of HCC [32]. Previous studies suggested that abnormal expression levels of several CYPs are involved in individualized treatment and prognosis of patients with HCC [4,7]. However, the exact roles of key CYP members in HCC must be clari ed.…”

“…A previous study reported that abnormal regulation of cytochrome P450 expression and activities in HCC have implications to personalized treatment [4][5][6]. Moreover, CYP2C8 [7], CYP2C9 [8], the CYP3A subfamily [9], and CYP4A11 [10] are reportedly closely related to HCC prognosis and survival.…”