Gustafsson B E, Einarsson K, Gustafsson J
J Biol Chem. 1975 Nov 10;250(21):8496-502.
The present investigation has aimed at defining the factor responsible for the differences in microsomal metabolism of steroids between germ-free and conventional rats. Cholesterol, cholic acid, taurocholic acid, and chenodeoxycholic acid were fed to conventional and germ-free male rats and the effects on liver microsomal metabolism of 4-[4-14C]androstene-3,17-dione, 5alpha-[4-14C]androstane-3alpha,17beta-diol, [4-14C]-cholesterol, 7alpha-hydroxy-4-[6beta-3H]cholesten-3-one, and [24-14C]lithocholic acid were studied. The most consistent effects were found with dietary cholesterol that stimulated the activities of several of the hydroxylases active on 4-androstene-3,17-dione and 5alpha-androstane-3alpha,17beta-diol and that decreased the 5alpha reduction of 4-androstene-3,17-dione, increased the 7alpha hydroxylation of cholesterol, decreased the 12alpha hydroxylation of 7alpha-hydroxy-4-cholesten-3-one, and increased by 6beta hydroxylation of lithocholic acid. These effects of cholesterol feeding on the microsomal metabolism of steroids in conventional rats made the pattern of microsomal enzyme activities resemble that characteristic of germ-free rats. Cholesterol feeding led to a pronounced increase in the intestinal concentration of beta-muricholic acid in conventional rats. Furthermore, cholesterol feeding to conventional animals led to an intestinal ratio of chenodeoxycholic acid (including its metabolites alpha- and beta-muricholic acid and hyodeoxycholic acid) to cholic acid (including deoxycholic acid) that was almost identical to that in germ-free rats. Conventionalization of germ-free rats for a period of up to 56 days led only to a partial normalization of the liver microsomal metabolism of 5alpha-[4-14C]androstane-3alpha, 17beta-diol and 7alpha-hydroxy-4-[6beta-3H]cholesten-3-one and of the liver microsomal concentration of cytochrome P-450. The concentration of cholesterol was higher in both total liver homogenate and liver microsomal fraction of germ-free rats than in corresponding preparations from conventional rats. In conclusion, it is suggested that cholesterol is one of the factors responsible for the different microsomal metabolism of steroids in germ-free and conventional rats. It is also suggested that cholesterol may play a role as regulator of microsomal enzyme activities.
本研究旨在确定造成无菌大鼠和普通大鼠甾体微粒体代谢差异的因素。将胆固醇、胆酸、牛磺胆酸和鹅去氧胆酸分别喂给普通雄性大鼠和无菌雄性大鼠，研究其对4-[4-¹⁴C]雄甾烯-3,17-二酮、5α-[4-¹⁴C]雄甾烷-3α,17β-二醇、[4-¹⁴C]胆固醇、7α-羟基-4-[6β-³H]胆甾烯-3-酮和[24-¹⁴C]石胆酸肝脏微粒体代谢的影响。研究发现，膳食胆固醇产生的影响最为一致，它刺激了几种作用于4-雄甾烯-3,17-二酮和5α-雄甾烷-3α,17β-二醇的羟化酶的活性，降低了4-雄甾烯-3,17-二酮的5α还原作用，增加了胆固醇的7α羟化作用，降低了7α-羟基-4-胆甾烯-3-酮的12α羟化作用，并增加了石胆酸的6β羟化作用。在普通大鼠中，膳食胆固醇对甾体微粒体代谢的这些影响使微粒体酶活性模式类似于无菌大鼠的特征模式。喂食胆固醇导致普通大鼠肠道中β-鼠胆酸浓度显著增加。此外，给普通动物喂食胆固醇导致肠道中鹅去氧胆酸（包括其代谢物α-和β-鼠胆酸以及猪去氧胆酸）与胆酸（包括脱氧胆酸）的比例几乎与无菌大鼠相同。将无菌大鼠普通化长达56天仅导致5α-[4-¹⁴C]雄甾烷-3α,17β-二醇和7α-羟基-4-[6β-³H]胆甾烯-3-酮的肝脏微粒体代谢以及细胞色素P-450的肝脏微粒体浓度部分恢复正常。无菌大鼠的全肝匀浆和肝脏微粒体部分中的胆固醇浓度均高于普通大鼠相应制剂中的胆固醇浓度。总之，提示胆固醇是造成无菌大鼠和普通大鼠甾体微粒体代谢不同的因素之一。还提示胆固醇可能作为微粒体酶活性的调节剂发挥作用。
