title: Strain differences in cytochrome P450 mRNA and protein expression, and enzymatic activity among Sprague Dawley, Wistar, Brown Norway and Dark Agouti rats.
abstract: Rat cytochrome P450 (CYP) exhibits inter-strain differences, but their analysis has been scattered across studies under different conditions. To identify these strain differences in CYP more comprehensively, mRNA expression, protein expression and metabolic activity among Wistar (WI), Sprague Dawley (SD), Dark Agouti (DA) and Brown Norway (BN) rats were compared. The mRNA level and enzymatic activity of CYP1A1 were highest in SD rats. The rank order of Cyp3a2 mRNA expression mirrored its protein expression, i.e., DA>BN>SD>WI, and was similar to the CYP3A2-dependent warfarin metabolic activity, i.e., DA>SD>BN>WI. These results suggest that the strain differences in CYP3A2 enzymatic activity are caused by differences in mRNA expression. Cyp2b1 mRNA levels, which were higher in DA rats, did not correlate with its protein expression or enzymatic activity. This suggests that the strain differences in enzymatic activity are not related to Cyp2b1 mRNA expression. In conclusion, WI rats tended to have the lowest CYP1A1, 2B1 and 3A2 mRNA expression, protein expression and enzymatic activity among the strains. In addition, SD rats had the highest CYP1A1 mRNA expression and activity, while DA rats had higher CYP2B1 and CYP3A2 mRNA and protein expression. These inter-strain differences in CYP could influence pharmacokinetic considerations in preclinical toxicological studies.
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, 18 W9, Kita-ku, Sapporo 060-0818, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Shouta M M
authors.initials: SM
authors.lastname: Nakayama
authors.forename: Kensuke P
authors.initials: KP
authors.lastname: Watanabe
authors.forename: Yusuke K
authors.initials: YK
authors.lastname: Kawai
authors.forename: Marumi
authors.initials: M
authors.lastname: Ohno
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011914:Rats, Inbred BN / Q000235:genetics / Q000378:metabolism; D011919:Rats, Inbred Strains / Q000235:genetics* / Q000378:metabolism; D017207:Rats, Sprague-Dawley / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System