Inhibition of MDR3 Activity in Human Hepatocytes by Drugs Associated with Liver Injury.
MDR3 dysfunction is associated with liver diseases. We report here a novel MDR3 activity assay involving in situ biosynthesis in primary hepatocytes of deuterium (d9)-labeled PC and LC-MS/MS determination of transported extracellular PC-d9. Several drugs associated with DILI such as chlorpromazine, imipramine, itraconazole, haloperidol, ketoconazole, sequinavir, clotrimazole, ritonavir, and troglitazone inhibit MDR3 activity. MDR3 inhibition may play an important role in drug-induced cholestasis and vanishing bile duct syndrome. Several lines of evidence demonstrate that the reported assay is physiologically relevant and can be used to assess the potential of chemical entities and their metabolites to modulate MDR3 activity and/or PC biosynthesis in hepatocytes.
Biotranex LLC , Monmouth Junction, New Jersey 08852, United States.
Kan
K
He
Biotranex LLC , Monmouth Junction, New Jersey 08852, United States.
Lining
L
Cai
Biotranex LLC , Monmouth Junction, New Jersey 08852, United States.
Qin
Q
Shi
Biotranex LLC , Monmouth Junction, New Jersey 08852, United States.
Hao
H
Liu
Biotranex LLC , Monmouth Junction, New Jersey 08852, United States.
Thomas F
TF
Woolf
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003903:Deuterium / Q000737:chemistry; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017964:Itraconazole / Q000737:chemistry / Q000633:toxicity; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D013656:Taurocholic Acid / Q000633:toxicity; D014700:Verapamil / Q000737:chemistry / Q000633:toxicity
D018435:ATP Binding Cassette Transporter, Subfamily B; D010713:Phosphatidylcholines; D017964:Itraconazole; D013656:Taurocholic Acid; C095122:multidrug resistance protein 3; D003903:Deuterium; D014700:Verapamil