CYP450 drug inducibility in NAFLD via an in vitro hepatic model: Understanding drug-drug interactions in the fatty liver

Abstract

Drug-drug-interactions (DDIs) occur when a drug alters the metabolic rate, efficacy, and toxicity of concurrently used drugs. While almost 1 in 4 adults now use at least 3 concurrent prescription drugs in the United States, the Non-alcoholic fatty liver disease (NAFLD) prevalence has also risen over 25%. The effect of NALFD on DDIs is largely unknown. NAFLD is characterized by lipid vesicle accumulation in the liver, which can progress to severe steatohepatitis (NASH), fibrosis, cirrhosis, and hepatic carcinoma. The CYP450 enzyme family dysregulation in NAFLD, which might already alter the efficacy and toxicity of drugs, has been partially characterized. Nevertheless, the drug-induced dysregulation of CYP450 enzymes has not been studied in the fatty liver. These changes in enzymatic inducibility during NAFLD, when taking concurrent drugs, could cause unexpected fatalities through inadvertent DDIs. We have, thus, developed an in vitro model to investigate the CYP450 transcriptional regulation in NAFLD. Specifically, we cultured primary human hepatocytes in a medium containing free fatty acids, high glucose, and insulin for seven days. These cultures displayed intracellular macro-steatosis after 5 days and cytokine secretion resembling NAFLD patients. We further verified the model’s dysregulation in the transcription of key CYP450 enzymes. We then exposed the NAFLD model to the drug inducers rifampicin, Omeprazole, and Phenytoin as activators of transcription factors pregnane X receptor (PXR), aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR), respectively. In the NAFLD model, Omeprazole maintained an expected induction of CYP1A1, however Phenytoin and Rifampicin showed elevated induction of CYP2B6 and CYP2C9 compared to healthy cultures. We, thus, conclude that the fatty liver could cause aggravated drug-drug interactions in NAFLD or NASH patients related to CYP2B6 and CYP2C9 enzymes.

Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study

“…Additionally, information on alterations to biotransformation enzymes can provide insight into the possibility of PFAS exposure causing disruptions to endogenous functions and drug metabolism by CYP450 enzymes. CYP enzymes play a crucial role in the metabolism of xenobiotics, and changes in their activity or expression can affect the toxicity and efficacy of pharmaceuticals ( Rey-Bedon et al 2022 ). Disruptions to biotransformation pathways can also lead to dysfunctions in intracellular processes created by an inability to regulate fatty acid metabolism and the accumulation of unmetabolized harmful substrates ( Deodhar et al 2020 ).…”

Could Alcohol Abuse and Dependence on Junk Foods Inducing Obesity and/or Illicit Drug Use Represent Danger to Liver in Young People with Altered Psychological/Relational Spheres or Emotional Problems?

“…Secondly, authors in various pieces of research have concluded that liver fat excess could cause severe drug–drug interactions in patients with obesity-related NAFLD or nonalcoholic steatohepatitis. These interactions are related to the CYP2B6 and CYP2C9 enzymes [ 154 , 155 , 156 ]. The generation of ROS inside and outside of hepatocytes, the formation of reactive metabolites at hepatic level, the modification of covalent bonds between constituents of cells with drugs and their metabolites, the activation of signal transduction pathways that alter necrosis or apoptosis or survival pathways, characterised by wide-ranging changes in gene expression (i.e., impacting on the regulation of transcriptional and post-transcriptional activities) coupled with mitochondrial damage, which ends up in altering ATP generation, are all principal mechanisms of drug-induced hepatotoxicity [ 157 ].…”

Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism

“…For instance, experimental and clinical studies report consistently that CYP3A4 is downregulated in fatty liver in terms of either activity, expression level, or pharmacokinetics (PK) 9 – 13 . In contrast, most but not all human and animal studies state that CYP2E1 is upregulated in non-alcoholic steatohepatitis in terms of either activity or expression 9 , 10 , 14 – 16 . In contrast, it was also observed in patients that CYP2E1 is downregulated in terms of protein and mRNA expression 17 .…”