Alcohol Cirrhosis Alters Nuclear Receptor and Drug Transporter Expression in Human Liver

Abstract

Unsafe use of alcohol results in approximately 2.5 million deaths worldwide, with cirrhosis contributing to 16.6% of reported deaths. Serum insulin levels are often elevated in alcoholism and may result in diabetes, which is why alcoholic liver disease and diabetes often are present together. Because there is a sizable population with these diseases alone or in combination, the purpose of this study was to determine whether transporter expression in human liver is affected by alcoholic cirrhosis, diabetes, and alcoholic cirrhosis coexisting with diabetes. Transporters aid in hepatobiliary excretion of many drugs and toxic chemicals and can be determinants of drug-induced liver injury. Drug transporter expression and transcription factor-relative mRNA and protein expression in normal, diabetic, cirrhotic, and cirrhosis with diabetes human livers were quantified. Cirrhosis significantly increased ABCC4, 5, ABCG2, and solute carrier organic anion (SLCO) 2B1 mRNA expression and decreased SLCO1B3 mRNA expression in the liver. ABCC1, 3-5, and ABCG2 protein expression was also upregulated by alcoholic cirrhosis. ABCC3-5 and ABCG2 protein expression was also upregulated in diabetic cirrhosis. Cirrhosis increased nuclear factor E2-related factor 2 mRNA expression, whereas it decreased pregnane-X-receptor and farnesoid-X-receptor mRNA expression in comparison with normal livers. Hierarchical cluster analysis indicated that expressions of ABCC2, 3, and 6; SLCO1B1 and 1B3; and ABCC4 and 5 were more closely related in the livers from this cohort. Overall, alcoholic cirrhosis altered transporter expression in human liver.

Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics

“…The expression of other transporters was not affected by cirrhosis. These results differ from previous studies in which the mRNA and protein expression of some of these transporters was determined (Ogasawara et al, 2010;More et al, 2013). Ogasawara et al reported that the mRNA expression of BCRP, MATE1, MRP2, MRP3, OATP1B1, 1B3, 2B1, and OCT1 was significantly reduced in hepatitis C cirrhosis livers versus control livers.…”

“…Ogasawara et al reported that the mRNA expression of BCRP, MATE1, MRP2, MRP3, OATP1B1, 1B3, 2B1, and OCT1 was significantly reduced in hepatitis C cirrhosis livers versus control livers. Another study, in a limited number of alcoholic cirrhosis livers (n = 10), found that BCRP, MRP1, and MRP3-5 protein expression (but not that of MRP2 or MRP6) was elevated (More et al, 2013). The reasons for the discrepancies between these data and our data are not known but could be differences in ethnicity (Japanese versus Caucasian liver tissues), endpoints (mRNA versus protein expression), and severity of the disease or sample size.…”

“…Clinical studies confirm that the urinary metabolic ratio of caffeine, mephenytoin, debrisoquine, and chlorzoxazone, which are in vivo probes of CYP1A2, 2C9, 2D6, and 2E1, respectively, is reduced (Ohnishi et al, 2005;Frye et al, 2006). However, there is a paucity of data on the effect of cirrhosis on expression and activity of hepatic drug transporters (Ogasawara et al, 2010;More et al, 2013). Therefore, using quantitative proteomics, we quantified the protein expression of the major hepatobiliary transporters in liver tissue obtained from patients with alcoholic and hepatitis C cirrhosis.…”

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

“…Combined with the results from our study, it is likely that the observed down-regulation of the Nrf2-mediated response in the early study was due to the upregulation of Hrd1 by tunicamycin. Inconsistent with our data, a recent study comparing gene expression profiles from human liver tissues from normal, steatosis, alcohol cirrhosis, and diabetic cirrhosis showed increased Nrf2 levels and increased downstream genes in alcoholic and diabetic cirrhotic livers compared with normal nonsteatotic livers (More et al 2013). The alcoholic cirrhotic liver tissues used in this study are from the same repository as ours.…”

Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment

“…Up-regulation of P-gp efflux transporters as an adaptive mechanism to limit the accumulation of toxic biliary constituents has been observed in liver samples from patients with advanced primary biliary cirrhosis [13]. Higher BCRP mRNA and protein expression has also been observed in liver tissue from subjects with alcoholic or diabetic cirrhosis [14]. The up-regulation of these efflux transporters could explain the decrease in ombitasvir exposures in subjects with hepatic impairment in this study.…”