Sorafenib Metabolism Is Significantly Altered in the Liver Tumor Tissue of Hepatocellular Carcinoma Patient

Abstract

BackgroundSorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC), is metabolized by cytochrome P450 (CYP) 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT) 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients.MethodsSorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs) and adjacent normal hepatic microsomes (NHLMs) of HCC patients (n = 18). Commercial hepatic microsomes (CHLMs) were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting.ResultsThe mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax) of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold) than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients’ samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs.ConclusionsSorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

Quantitative Profiling of Human Renal UDP-glucuronosyltransferases and Glucuronidation Activity: A Comparison of Normal and Tumoral Kidney Tissues

“…The biologic impact of locally reduced glucuronidation capacity in diseased tissues remains to be examined but could be of clinical relevance to susceptibility to kidney cancer or treatment of kidney cancer. The important loss of UGT1A9-and UGT2B7-conjugating activity in tumor kidneys is in line with the reduced expression of several UGT1A and UGT2B7 observed at both mRNA and protein levels in hepatocellular carcinomas (Strassburg et al, 1997;Yan et al, 2014;Ye et al, 2014), UGT1A10 and UGT2B7 in breast cancer Fig. 6.…”

“…The decreased glucuronidation activity of kidney tumors relative to normal tissues is of particular relevance in advanced renal clear cell carcinoma treatment strategies, given that sorafenib is an important renal carcinoma anticancer agent (Escudier et al, 2007;Zustovich et al, 2011). It is primarily metabolized by CYP3A4 and UGT1A9 in the liver, but its renal metabolism has not been assessed (Keating and Santoro, 2009;Ye et al, 2014). The biologic impact of locally reduced glucuronidation capacity in diseased tissues remains to be examined but could be of clinical relevance to susceptibility to kidney cancer or treatment of kidney cancer.…”

Proliferation of sphere-forming hepatocellular carcinoma cells is suppressed in a medium without glucose and arginine, but with galactose and ornithine

“…Sorafenib is metabolized by CYP3A4 (10). In the present study, the expression levels of CYP3A4 were observed to increase during sphere formation.…”

“…Sorafenib is a multikinase inhibitor with a high antitumor efficacy that suppresses cell proliferation and induces apoptosis in HCC cell lines (5)(6)(7). A limitation of this approach is that HCC cells acquire resistance to sorafenib (8,9), as it is metabolized by cytochrome P450 (CYP3A4) (10). This has necessitated the development of alternative therapies for HCC.…”

Pseudocirrhosis caused by regorafenib in an advanced rectal cancer patient with multiple liver metastases

“…Sorafenib is also metabolized by CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation. Ye et al (8) reported that sorafenib metabolism was significantly altered in the liver tumor tissue of a hepatocellular carcinoma patient, due to an evident decrease of the expression level of CYP3A4 and UGT1A9. Boudou-Rouquette et al (9) reported that the UGT1A9 polymorphism (rs17868320) was WBC, white blood cell; RBC, red blood cell; PLT, platelet; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; γ-GTP, γ-glutamyl transpeptidase; BUN, blood urea nitrogen; HPT, heparin protamine titration; PT, prothrombin time; PTINR, prothrombin time/international normalized ratio; APTT, activated partial thromboplastin time; ATIII, antithrombin III; FDP, fibrin degradation products.…”