PT - JOURNAL ARTICLE AU - Yuan Wei AU - Li Yang AU - Xiaoyan Zhang AU - Danjuan Sui AU - Changsuo Wang AU - Kai Wang AU - Mangting Shan AU - Dayong Guo AU - Hongyu Wang TI - Generation and Characterization of a CYP2C11-null Rat Model by using the CRISPR/Cas9 method AID - 10.1124/dmd.117.078444 DP - 2018 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.117.078444 4099 - http://dmd.aspetjournals.org/content/early/2018/02/14/dmd.117.078444.short 4100 - http://dmd.aspetjournals.org/content/early/2018/02/14/dmd.117.078444.full AB - CYP2C11 is involved in the metabolism of many drugs in rats. To assess the roles of CYP2C11 in physiology and drug metabolism, a CYP2C11-null rat model was generated using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 method. A 2-bp insertion was added to exon 6 of CYP2C11 in Sprague-Dawley rats. CYP2C11 was not detected by Western blotting in liver microsomes of CYP2C11-null rats. No off-target effects were found at eleven predicted sites of the knockout model. The CYP2C11-null rats were viable and had no obvious abnormalities, with the exception of reduced fertility. Puberty in CYP2C11-null rats appeared to be delayed by ~20 days, and the average litter size fell by 43%. Tolbutamide was used as a probe in this drug metabolism study. In the liver microsomes of CYP2C11-null rats, Vmax and CLint decreased by ~21% and ~44%, respectively, compared to those of wild-type rats. The Km increased by 138% compared to that of wild-types. However, our pharmacokinetics study showed no major differences in any parameters between the two strains, in both males and females. In conclusion, a CYP2C11-null rat model was successfully generated and is a valuable tool to study the in vivo function of CYP2C11.