Effects of Nonalcoholic Fatty Liver Disease on Hepatic CYP2B1 and in Vivo Bupropion Disposition in Rats Fed a High-Fat or Methionine/Choline-Deficient Diet.
Nonalcoholic fatty liver disease (NAFLD) refers to hepatic pathologies, including simple fatty liver (SFL), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, that may progress to hepatocellular carcinoma. These liver disease states may affect the activity and expression levels of drug-metabolizing enzymes, potentially resulting in an alteration in the pharmacokinetics, therapeutic efficacy, and safety of drugs. This study investigated the hepatic cytochrome P450 (CYP) 2B1-modulating effect of a specific NAFLD state in dietary rat models. Sprague-Dawley rats were given a methionine/choline-deficient (MCD) or high-fat (HF) diet to induce NASH and SFL, respectively. The induction of these disease states was confirmed by plasma chemistry and liver histological analysis. Both the protein and mRNA levels of hepatic CYP2B1 were considerably reduced in MCD diet-fed rats; however, they were similar between the HF diet-fed and control rats. Consistently, the enzyme-kinetic and pharmacokinetic parameters for CYP2B1-mediated bupropion metabolism were considerably reduced in MCD diet-fed rats; however, they were also similar between the HF diet-fed and control rats. These results may promote a better understanding of the influence of NAFLD on CYP2B1-mediated metabolism, which could have important implications for the safety and pharmacokinetics of drug substrates for the CYP2B subfamily in patients with NAFLD.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul 08826, Republic of Korea.
Sung-Joon
SJ
Cho
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul 08826, Republic of Korea.
Sang-Bum
SB
Kim
College of Pharmacy, Kangwon National University , Gangwon 24341, Republic of Korea.
Hyun-Jong
HJ
Cho
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul 08826, Republic of Korea.
Saeho
S
Chong
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul 08826, Republic of Korea.
Suk-Jae
SJ
Chung
Advanced Geo-materials R&D Department, Korea Institute of Geoscience and Mineral Resources, Pohang Branch , Gyeongbuk 37559, Republic of Korea.
Il-Mo
IM
Kang
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul 08826, Republic of Korea.
Jangik Ike
JI
Lee
College of Pharmacy and Natural Medicine Research Institute, Mokpo National University , Jeonnam 58554, Republic of Korea.
In-Soo
IS
Yoon
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul 08826, Republic of Korea.
Dae-Duk
DD
Kim
D000818:Animals; D016642:Bupropion / Q000008:administration & dosage*; D002794:Choline / Q000378:metabolism; D002796:Choline Deficiency / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000172:deficiency*; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016642:Bupropion; D008715:Methionine; D019362:Cytochrome P-450 CYP2B1; D002794:Choline
CYP2B1; bupropion; high-fat diet; methionine/choline-deficient diet; nonalcoholic fatty liver disease