Davies M H, Ngong J M, Yucesoy M, Acharya S K, Mills C O, Weaver J B, Waring R H, Elias E
Queen Elizabeth Hospital, Department of Biochemistry, University of Birmingham, UK.
J Hepatol. 1994 Dec;21(6):1127-34. doi: 10.1016/s0168-8278(05)80630-0.
Sulphation of oestrogens and monohydroxy bile acids is important in attenuating their cholestatic potential. Thus, impairment of sulphation could lead to retention of cholestatic compounds and precipitate intrahepatic cholestasis in susceptible individuals. We tested the hypothesis that such a mechanism may be involved in the pathogenesis of intrahepatic cholestasis of pregnancy. In vivo and in vitro assessment of sulphation capacity was performed in patients with cholestasis of pregnancy, compared with control females on and off the oestrogen-containing oral contraceptive pill and control individuals during normal pregnancy and post partum, to assess the influence of high oestrogen states upon this metabolic pathway. During in vivo studies utilising paracetamol as a metabolic probe, the proportion of paracetamol sulphate and sulphate: glucuronide ratio were decreased in those with elevated oestrogens, whether the rise in oestrogens was endogenous, in pregnancy (paracetamol sulphate p < 0.05; paracetamol sulphate:glucuronide ratio p < 0.01), or exogenous, with the contraceptive pill (paracetamol sulphate p = 0.2; paracetamol sulphate:glucuronide ratio p < 0.001). In vitro, platelet sulphotransferase activity was measured, utilising phenol as substrate. Sulphotransferase activity decreased during pregnancy compared with repeat measurements post partum (p < 0.005) and compared with non-pregnant individuals (p < 0.05). In conclusion, we have shown that elevated oestrogens are associated with significant impairment in sulphation capacity. An imbalance of sulphation with glucuronidation provoked by high circulating oestrogen levels may be contributory in the pathogenesis of cholestasis of pregnancy.
雌激素和单羟基胆汁酸的硫酸化对于减弱它们的胆汁淤积潜能很重要。因此，硫酸化功能受损可能导致胆汁淤积性化合物潴留，并在易感个体中引发肝内胆汁淤积。我们检验了这样一种机制可能参与妊娠期肝内胆汁淤积症发病过程的假说。对妊娠期胆汁淤积症患者进行了体内和体外硫酸化能力评估，并与正在服用和停用含雌激素口服避孕药的对照女性以及正常妊娠和产后的对照个体进行比较，以评估高雌激素状态对这一代谢途径的影响。在利用对乙酰氨基酚作为代谢探针的体内研究中，无论雌激素升高是内源性的（妊娠期，对乙酰氨基酚硫酸盐p<0.05；对乙酰氨基酚硫酸盐：葡萄糖醛酸苷比率p<0.01）还是外源性的（服用避孕药，对乙酰氨基酚硫酸盐p = 0.2；对乙酰氨基酚硫酸盐：葡萄糖醛酸苷比率p<0.001），雌激素升高者的对乙酰氨基酚硫酸盐比例和硫酸盐：葡萄糖醛酸苷比率均降低。在体外，以苯酚为底物测量血小板磺基转移酶活性。与产后重复测量相比（p<0.005）以及与未孕个体相比（p<0.05），妊娠期磺基转移酶活性降低。总之，我们已表明雌激素升高与硫酸化能力的显著受损有关。高循环雌激素水平引发的硫酸化与葡萄糖醛酸化失衡可能在妊娠期胆汁淤积症的发病过程中起作用。
