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Nonalcoholic Fatty Liver Disease and Diabetes Are Associated with Decreased CYP3A4 Protein Expression and Activity in Human Liver
journal contribution
posted on 2018-05-24, 00:00 authored by Rohitash Jamwal, Suzanne M. de la Monte, Ken Ogasawara, Sravani Adusumalli, Benjamin B. Barlock, Fatemeh AkhlaghiNonalcoholic fatty liver disease
(NAFLD) is a major cause of chronic
liver disease in the Western population. We investigated the association
of nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus
on CYP3A4 activity in human liver tissue from brain dead donors (n = 74). Histopathologically graded livers were grouped
into normal (n = 24), nonalcoholic fatty liver (NAFL, n = 26), and nonalcoholic steatohepatitis (NASH, n = 24) categories. The rate of conversion of midazolam
to its 1-hydroxy metabolite was used to assess in vitro CYP3A4 activity in human liver microsomes (HLM). A proteomics approach
was utilized to quantify the protein expression of CYP3A4 and related
enzymes. Moreover, a physiologically based pharmacokinetic (PBPK)
model was developed to allow prediction of midazolam concentration
in NAFL and NASH livers. CYP3A4 activity in NAFL and NASH was 1.9-
and 3.1-fold (p < 0.05) lower than normal donors,
respectively. Intrinsic clearance (CLint) was 2.7- (p < 0.05) and 4.1-fold (p < 0.01) lower in
donors with NAFL and NASH, respectively. CYP3A4 protein expression
was significantly lower in NAFL and NASH donors (p < 0.05) and accounted for significant midazolam hydroxylation
variability in a multiple linear regression analysis (β = 0.869, r2 = 0.762, P < 0.01). Diabetes
was also associated with decreased CYP3A4 activity and protein expression.
Both midazolam CLint and CYP3A4 protein abundance decreased significantly
with increase in hepatic fat accumulation. Age and gender did not exhibit any significant
association with the observed alterations. Predicted midazolam exposure
was 1.7- and 2.3-fold higher for NAFL and NASH, respectively, which
may result in a longer period of sedation in these disease-states.
Data suggests that NAFLD and diabetes are associated with the decreased
hepatic CYP3A4 activity. Thus, further evaluation of clinical consequences
of these findings on the efficacy and safety of CYP3A4 substrates
is warranted.
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CYP 3A protein expressionPredicted midazolam exposureHuman Liver Nonalcoholicmidazolam hydroxylation variabilityCYP 3A protein abundanceNonalcoholic Fatty Liver DiseaseHLMNASHliver diseaseNAFLDDecreased CYP 3A Protein ExpressionCYP 3A substratesPBPKNAFLdonor1- hydroxy metabolitehepatic CYP 3A activityCYP 3A activityprotein expression
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