Role of cytochrome P450 1A2 in bilirubin degradation - Studies in Cyp1a2 (-/-) mutant mice

In congenital jaundice, which is due to defects of bilirubin gluruconidatio n, bilirubin is degraded by an alternative pathway into unidentified produc ts. Previously, it was shown that plasma bilirubin levels can be decreased in rats with this defect by inducers of CYP1A enzymes. Here, liver microsom es from rats or mice treated with beta -naphthoflavone (BNF) or 3-methylcho lanthrene (3 MC) had increased activity for bilirubin degradation. The acti vity was further stimulated by addition of the coplanar molecule 3,4,3',4'- tetrachlorobiphenyl (TCB). There was more stimulation of bilirubin degradat ion by TCB in microsomes from BNF-treated rats than in microsomes from BNF- treated mice. CYPIA1 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. Betw een SWR and C57BL/6 inbred mouse strains that have a 2-fold difference in h epatic constitutive CYP1A2 levels, there was also a 2-fold difference in bi lirubin degradation; TCB did not stimulate in either strain. We conclude th at CYP1A2 is responsible for microsomal bilirubin degradation in the absenc e of TCB. TCB was required for bilirubin degradation by CYP1A1. Manipulatio n of CYP1A2 may be of therapeutic benefit in patients with these diseases o f bilirubin conjugation. (C) 2001 Elsevier Science Inc. All rights reserved .