Meredith C G, Muhoberac B B, Gray J P, Speeg K V, Dunn D, Hoyumpa A M, Schenker S
Biochem Pharmacol. 1986 Nov 1;35(21):3831-7. doi: 10.1016/0006-2952(86)90672-6.
The aims of this study were to evaluate the hypothesis that impaired glucuronidation of bilirubin and possibly of drug oxidation in the liver of homozygous (jj) Gunn rats may be due to an altered microsomal milieu. Accordingly, we investigated and compared in vivo and in vitro demethylation of aminopyrine, hepatic cytochrome P-450 levels, microsomal lipid composition, and microsomal membrane fluidity in icteric, homozygous (jj) Gunn rats and in their anicteric heterozygous (jJ) littermates. In both males and females, [14C]aminopyrine demethylation in vivo, using the 14CO2 breath test, was unimpaired in the icteric animals. Likewise, cytochrome P-450 levels in the icteric and nonicteric groups were similar, and aminopyrine kinetics in vitro in the females were comparable in icteric and nonicteric littermates. The main lipid classes were also similar in the homozygous and heterozygous female Gunn rats, whereas only minor changes were seen in the phospholipid fatty acyl composition with a small, but significant, increase in the unsaturated index in the icteric group. Despite this, there was no apparent effect on hepatic microsomal membrane fluidity as measured by the order parameter of I[12,3] and the rotational correlation time of I[1,14] in either female or male sets of homozygous and heterozygous Gunn rats. Our data, therefore, do not support an alteration of composition or fluidity of the microsomal milieu as a mechanism of impaired bilirubin glucuronidation and possibly of oxidation in these animals. They also absolve long-term unconjugated hyperbilirubinemia as a mechanism of hepatic microsomal dysfunction. Our study, therefore, indirectly suggests that abnormal glucuronidation of bilirubin and some other aglycones in homozygous Gunn rats is due to genetic abnormalities involving the enzyme(s) itself.
纯合子（jj）Gunn大鼠肝脏中胆红素葡萄糖醛酸化受损以及可能的药物氧化受损，可能是由于微粒体环境改变所致。因此，我们研究并比较了黄疸型纯合子（jj）Gunn大鼠及其无黄疸型杂合子（jJ）同窝仔鼠体内和体外氨基比林的脱甲基作用、肝细胞色素P-450水平、微粒体脂质组成以及微粒体膜流动性。在雄性和雌性大鼠中，通过14CO2呼气试验检测，黄疸型动物体内[14C]氨基比林的脱甲基作用未受损害。同样，黄疸型和非黄疸型组的细胞色素P-450水平相似，雌性大鼠体内黄疸型和非黄疸型同窝仔鼠体外氨基比林的动力学也相当。纯合子和杂合子雌性Gunn大鼠的主要脂质类别也相似，而在磷脂脂肪酸酰基组成方面仅观察到微小变化，黄疸型组的不饱和指数有小幅但显著的增加。尽管如此，无论是雌性还是雄性纯合子和杂合子Gunn大鼠组，通过I[12,3]的有序参数和I[1,14]的旋转相关时间测量，肝微粒体膜流动性均未出现明显变化。因此，我们的数据不支持微粒体环境的组成或流动性改变是这些动物胆红素葡萄糖醛酸化受损以及可能的氧化受损机制的观点。这些数据也排除了长期未结合高胆红素血症作为肝微粒体功能障碍机制的可能性。因此，我们的研究间接表明，纯合子Gunn大鼠中胆红素和其他一些苷元的异常葡萄糖醛酸化是由于涉及该酶本身的基因异常所致。
