RT Journal Article
SR Electronic
T1 Generation and Characterization of a CYP2C11-null Rat Model by using the CRISPR/Cas9 method
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.078444
DO 10.1124/dmd.117.078444
A1 Yuan Wei
A1 Li Yang
A1 Xiaoyan Zhang
A1 Danjuan Sui
A1 Changsuo Wang
A1 Kai Wang
A1 Mangting Shan
A1 Dayong Guo
A1 Hongyu Wang
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/02/14/dmd.117.078444.abstract
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.