Kitareewan S, Walz F G
Department of Chemistry, Kent State University, OH 44242.
Drug Metab Dispos. 1994 Jul-Aug;22(4):607-15.
Hepatic microsomes from immature and sexually mature male and female ACI/SEGHsd, F344/NHsd, SHR/NHsd, and WKY/NCrl inbred rats were used to study cytochrome P450 (P450)-catalyzed oxidations of progesterone and both enantiomers of warfarin. Strains were selected on the basis of their different, homozygous allelic compositions for CYP2C11 and CYP2C13 (Rampersaud and Walz, 1992), but no correlations with the microsomal activities were observed. However, correlations were made regarding catalytic activities and the developmental control of CYP2A1 and CYP2C11 levels in microsomes. Other correlations were found for reactions of both warfarin enantiomers at the same atom or for a given enantiomer at different positions, and these appear to involve several P450 isozymes. Strain-dependent activity differences mainly involved the SHR/NHsd and WKY/NCrl strains. WKY/NCrl rats were the most unique strain, having low levels of CYP2C11 in adult males compared with the other inbreds but relatively high S-warfarin 4'- and 6-hydroxylase activities in immature animals of both sexes and adult females. These results suggest that the regulation and/or allozymic composition of hepatic P450s are different for WKY/NCrl rats, which makes them a poor choice as "normotensive controls" in comparison with hypertensive SHR rats.
利用未成熟及性成熟的雄性和雌性ACI/SEGHsd、F344/NHsd、SHR/NHsd和WKY/NCrl近交系大鼠的肝微粒体，研究细胞色素P450（P450）催化的孕酮及华法林两种对映体的氧化反应。根据CYP2C11和CYP2C13不同的纯合等位基因组成选择品系（Rampersaud和Walz，1992），但未观察到与微粒体活性的相关性。然而，对微粒体中CYP2A1和CYP2C11水平的催化活性及发育调控进行了相关性分析。还发现了华法林两种对映体在同一原子上的反应或给定对映体在不同位置的反应之间的其他相关性，这些似乎涉及几种P450同工酶。品系依赖性活性差异主要涉及SHR/NHsd和WKY/NCrl品系。WKY/NCrl大鼠是最独特的品系，与其他近交系相比，成年雄性大鼠CYP2C11水平较低，但在未成熟的雌雄大鼠及成年雌性大鼠中，S-华法林4'-和6-羟化酶活性相对较高。这些结果表明，WKY/NCrl大鼠肝脏P450的调控和/或同工酶组成不同，这使得它们与高血压SHR大鼠相比，作为“正常血压对照”不是一个好的选择。
