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Nonalcoholic fatty liver disease and diabetes is associated with decreased CYP3A4 protein expression and activity in human liver Rohitash Jamwal, Suzanne M. de la Monte, Ken Ogasawara, Sravani Adusumalli, Benjamin B Barlock, and Fatemeh Akhlaghi Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00159 • Publication Date (Web): 24 May 2018 Downloaded from http://pubs.acs.org on May 27, 2018
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Molecular Pharmaceutics
Nonalcoholic fatty liver disease and diabetes is associated with decreased CYP3A4 protein expression and activity in human liver Rohitash Jamwal 1, Suzanne M. de la Monte 2, Ken Ogasawara 1, Sravani Adusumalli 1, Benjamin B Barlock 1, Fatemeh Akhlaghi 1 1
Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island,
Kingston, RI, 02881, USA 2
Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and
the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. Corresponding author at: Fatemeh Akhlaghi, Ph.D. Clinical Pharmacokinetics Research Laboratory Department of Biomedical and Pharmaceutical Sciences The University of Rhode Island, 495A College of Pharmacy, 7 Greenhouse Road, Kingston, RI 02881, United States. Email address:
[email protected] 1 ACS Paragon Plus Environment
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The number of words in the abstract: 276 The number of words in the introduction: 788 The number of words in the discussion: 1601 The number of figures: 6 The number of tables: 4 The number of references: 78 The number of supplemental tables: 5 The number of supplemental figures: 5
List of abbreviations in the order of appearance BMI: Body mass index; CAR: Constitutive androstane receptor; CPR:NADPH-cytochrome P450 reductase, Cyb5:Cytochrome b5; CYP3A: Cytochrome P450 3A; CYP3A4: Cytochrome P450 3A4; CYP3A5: Cytochrome P450 3A5; CYP3A43: Cytochrome P450 3A43; CYP3A7: Cytochrome P450 3A7; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HNF4α:Hepatocyte nuclear factor 4α; HLM: Human liver microsomes; NAFLD: Non-alcoholic fatty liver disease; NAFL: Non-alcoholic fatty liver; NASH: Non-alcoholic steatohepatitis; NADPH: Nicotinamide adenine dinucleotide phosphate; PCR: Polymerase chain reaction; PXR: Pregnane X receptor; TBARS: Thiobarbituric acid reactive substances; TOF: Time of flight; UPLC-MS: Ultra performance liquid chromatographymass spectrometer.
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Molecular Pharmaceutics
ABSTRACT Nonalcoholic 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 patients. CYP3A4 activity in NAFL and NASH was 1.9 and 3.1-fold (p
