Microsomal Cytochrome P450 Enzyme Activities in Nonalcoholic Steatohepatitis Livers

Microsomal Cytochrome P450 Enzyme Activities in Nonalcoholic Steatohepatitis Livers

Published:  7/16/2018 8:00:00 AM

Maciej Czerwinski1, Brian Oberheide1, Nicholas Hatfield1, Bill Ewy1, Christopher Seib1, Eva Gatineau2, Frederique Yiannikouris2, Brian Ogilvie1
1 Sekisui XenoTech, LLC
2 University of Kentucky, Department of Pharmacology and Nutritional Sciences


Abstract:
The prevalence of nonalcoholic steatohepatitis (NASH), a chronic liver disease, has increased drastically in parallel with the raise of obesity in the US. This condition affects hepatic drug metabolism and has potential to impact drug-drug interactions. Our study aimed to evaluate microsomal CYP enzyme activities, organ fibrosis and microvesicular steatosis in NASH tissues deposited in the Sekisui XenoTech Biobank, and to establish whether these tissues have application as an in vitro test system for the study of NASH impact on metabolism of xenobiotics. NASH tissues were identified based on the examination of hematoxylin and eosin (H&E), Masson’s trichrome staining and donor history of alcohol consumption. All samples had intra-lobular inflammation, ballooning necrosis and macrovesicular fat >5%. Fibrosis stage was assigned based on Brunt et al. The degree of microvesicular steatosis, evaluated by H&E staining, did not correlate with the body mass index (BMI) nor with progressive stages of fatty liver disease in 51 donors. However, the extent of microvesicular steatosis correlated positively with triglyceride contents (R2=0.66), but not with total cholesterol levels. Microsomal protein yield was weakly negatively correlated with microvesicular fat content (R2=0.11) but did not correlate with BMI. The majority of average microsomal CYP activities in NASH livers were lower than in the general population of liver donors by 6 to 65%. In contrast, the average CYP2E1 microsomal activity in NASH livers was 3.5% higher than in the general population of liver donors in the Biobank. These observations were in agreement with published clinical data. A microsomal pool of five NASH donors and tissue micro arrays containing NASH and fatty livers from donors with and without history of alcohol consumption were prepared to assist in disease evaluation. The NASH pattern of CYP enzyme activities seen in the patients and in the microsomes prepared from non-transplantable NASH livers suggest that the subcellular fraction is an appropriate test system for analysis of CYP-mediated xenobiotic metabolism associated with the disease state.

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