P49 T0901317-induced hepatic steatosis dramatically decreases CYP3A and CYP2C activities in mice

Jessica Virgili , Université Laval, Québec, QC, Canada
Sylvie Pilote , CRIUCPQ, Québec, QC, Canada
Camille Thibault , Université Laval, Québec, QC, Canada
Éric Jubinville , CRIUCPQ, Québec, QC, Canada
Joanie Routhier , Université Laval, Québec, QC, Canada
Benoît Drolet , Université Laval, Québec, QC, Canada
Mathieu C. Morissette , Université Laval, Québec, QC, Canada
Chantale Simard , Université Laval, Québec, QC, Canada
Background and objectives: Non-alcoholic fatty liver disease (NAFLD) is a common disorder strongly associated with metabolic syndrome components such as abdominal obesity and type II diabetes.1 Due to the rising tide of obesity, the burden of NAFLD is still increasing.2 NAFLD patients often use numerous drugs to manage comorbidities. Little is known about the effects of NAFLD on drug metabolism and disposition. An animal model with rapid onset of NAFLD would therefore be helpful to further characterize drug metabolism in this particular condition. With that in mind, to quickly generate such a preclinical model, we characterized the impact of T0901317, a liver X-receptor agonist, on the development of NAFLD in mice. The function of two major hepatic cytochrome P450 subfamilies (CYP3A and CYP2C) was evaluated. Methods: Seven to nine-week old female C57BL/6 mice were injected intraperitoneally daily for 4 days with either vehicle or T0901317 (T0) 20 mg/kg (n=5/group). Livers were collected, washed, weighted and snap frozen in liquid nitrogen. Frozen optical cutting temperature-embedded liver sections were stained with Oil red O. Microsomes were extracted, the protein content was determined and standard incubations were performed with either testosterone, a CYP3A probe substrate or tolbutamide, a CYP2C probe substrate. Results: T0 treatment caused a 1.8-fold increase in total liver weight compared to vehicle treatment. A marked lipid infiltration in the cytosol of hepatocytes, a hallmark of NAFLD, was also seen in T0-treated mice. In T0901317-treated mice, hepatic activities of CYP3A and CYP2C were significantly decreased by 78% (p<0.001) and 80% (p<0.01) respectively, when compared to vehicle-treated mice. Conclusions: Drug metabolism mediated by CYP3A and CYP2C subfamilies was drastically impaired in the T0901317-treated mice. These results further reinforce the notion that liver conditions such as NAFLD have a major impact on the metabolism of xenobiotics. Therefore, the T0901317-treated mouse could represent a quick and cost-effective animal model to investigate the effects of hepatic steatosis on drug metabolism, providing better understanding of the disease and potentially leading to personalized therapeutic strategies.

  1. Ballestri S et al. (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 31: 936-944.
  2. Lonardo a et al. (2017) AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig Liver Dis. http://dx.doi.org.acces.bibl.ulaval.ca/10.1016/j.dld.2017.01.147.