Zaccaro C, Sweitzer S, Pipino S, Gorman N, Sinclair P R, Sinclair J F, Nebert D W, De Matteis F
Department of Pharmacology, University of Turin Medical School, Via P. Giuria 13, 10125, Turin, Italy.
Biochem Pharmacol. 2001 Apr 1;61(7):843-9. doi: 10.1016/s0006-2952(01)00568-8.
In congenital jaundice, which is due to defects of bilirubin gluruconidation, bilirubin is degraded by an alternative pathway into unidentified products. Previously, it was shown that plasma bilirubin levels can be decreased in rats with this defect by inducers of CYP1A enzymes. Here, liver microsomes from rats or mice treated with beta-naphthoflavone (BNF) or 3-methylcholanthrene (3 MC) had increased activity for bilirubin degradation. The activity was further stimulated by addition of the coplanar molecule 3,4,3',4'-tetrachlorobiphenyl (TCB). There was more stimulation of bilirubin degradation by TCB in microsomes from BNF-treated rats than in microsomes from BNF-treated mice. CYP1A1 to CYP1A2 ratios were greater in rats treated with BNF. In Cyp1a2 (-/-) mutant mice, 3-MC treatment did not increase the rate of bilirubin degradation, but TCB increased this degradation severalfold. Between SWR and C57BL/6 inbred mouse strains that have a 2-fold difference in hepatic constitutive CYP1A2 levels, there was also a 2-fold difference in bilirubin degradation; TCB did not stimulate in either strain. We conclude that CYP1A2 is responsible for microsomal bilirubin degradation in the absence of TCB. TCB was required for bilirubin degradation by CYP1A1. Manipulation of CYP1A2 may be of therapeutic benefit in patients with these diseases of bilirubin conjugation.
在先天性黄疸中，由于胆红素葡萄糖醛酸化缺陷，胆红素通过另一条途径降解为不明产物。此前研究表明，患有这种缺陷的大鼠，其血浆胆红素水平可通过CYP1A酶诱导剂降低。在此，用β-萘黄酮（BNF）或3-甲基胆蒽（3 MC）处理的大鼠或小鼠的肝微粒体，其胆红素降解活性增加。添加共平面分子3,4,3',4'-四氯联苯（TCB）可进一步刺激该活性。与BNF处理的小鼠微粒体相比，BNF处理的大鼠微粒体中TCB对胆红素降解的刺激作用更强。用BNF处理的大鼠中CYP1A1与CYP1A2的比率更高。在Cyp1a2（-/-）突变小鼠中，3-MC处理并未增加胆红素降解速率，但TCB使这种降解增加了数倍。在肝组成型CYP1A2水平相差2倍的SWR和C57BL/6近交系小鼠品系之间，胆红素降解也相差2倍；TCB在这两个品系中均未产生刺激作用。我们得出结论，在没有TCB的情况下，CYP1A2负责微粒体胆红素降解。CYP1A1降解胆红素需要TCB。对CYP1A2进行调控可能对患有这些胆红素结合疾病的患者具有治疗益处。
