Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology

Abstract

Hepatic drug metabolizing enzymes (DMEs) markedly affect drug pharmacokinetics. Because liver diseases may alter enzymatic function and in turn drug handling and clinical efficacy, we investigated DMEs expression in dependence on liver pathology and liver failure state. In 5 liver pathologies (hepatitis C, alcoholic liver disease, autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis) and for the first time stratified according to the Child–Pugh score, 10 CYPs (CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) and 4 UGTs (UGT1A1, UGT1A3, UGT2B7 and UGT2B) enzymes were quantified for protein abundance (LC-MS/MS) and gene expression (qRT-PCR). CYP2E1 was the most vulnerable enzyme, and its protein levels were significantly reduced just in Child–Pugh class A livers. The protein abundance of CYP1A1, CYP2B6, CYP2C19, CYP2D6 as well as UGT1A1, UGT1A3 and UGT2B15 was relatively stable in the course of progression of liver function deterioration. Alcoholic liver disease and primary biliary cholangitis were involved in the most prominent changes in the protein abundances, with downregulation of 6 (CYP1A2, CYP2C8, CYP2D6, CYP2E1, CYP3A4, UGT2B7) and 5 (CYP1A1, CYP2B6, CYP2C8, CYP2E1, CYP3A4) significantly downregulated enzymes, respectively. The results of the study demonstrate that DMEs protein abundance is affected both by the type of liver pathology as well as functional state of the organ.

Considerations for Physiologically Based Modeling in Liver Disease: From Nonalcoholic Fatty Liver (NAFL) to Nonalcoholic Steatohepatitis (NASH)

“…8 , 9 Current dosing recommendations can be agnostic to CLD etiology, 7 which may differentially impact pharmacokinetics. 10 , 11 While NAFLD is a common cause of cirrhosis, only about 20% of patients with NASH progress to cirrhosis in their lifetime. 3 Despite increasing NAFLD prevalence in modern society and consistent data demonstrating progressive NAFLD‐mediated alterations in drug metabolizing enzymes (DMEs) and transporters, 12 patients with non‐cirrhotic fatty liver disease often are overlooked in premarketing pharmacokinetic studies and, accordingly, lack regulatory‐approved labeling recommendations for dosing.…”

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

“…Another possibility could be the loss of CYP2E1 induction during NAFLD progression ( Figure 2B ). Indeed, recent investigations suggested that CYP2E1 induction seems to wane when NASH progresses toward advanced fibrosis [ 57 ], in line with clinical data reporting a significant reduction of CYP2E1 expression with the progression of liver fibrosis [ 138 , 139 ]. Increased production of proinflammatory cytokines including TNF-α might play a role in this progressive decline of CYP2E1 expression [ 135 , 139 ].…”

Predicting changes in the pharmacokinetics of CYP3A‐metabolized drugs in hepatic impairment and insights into factors driving these changes

“…For example, the change in the expression of DMET in the liver depends on the etiology of the disease (e.g., alcoholic vs. hepatitis C cirrhosis). 7 , 9 , 10 , 11 , 12 , 13 …”

“… 18 With the advent of quantitative‐targeted proteomics, much progress has been made in the quantification of the abundance of DMET in HI. 7 , 9 , 10 , 11 , 12 , 13 However, to use these data with confidence, such quantification needs to be validated through phenotyping PK studies in this population. Such phenotyping studies can be conducted with probe drugs of the major DMET and interpreted to reflect changes in the in vivo activity of the DMET provided the rate‐determining step(s) in the CL of the drugs is (are) known.…”