Role of cytochrome P450 1A2 in bilirubin degradation Studies in Cyp1a2 (-/-) mutant mice.
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.
Zaccaro
C
C
Department of Pharmacology, University of Turin Medical School, Via P. Giuria 13, 10125, Turin, Italy.
Sweitzer
S
S
Pipino
S
S
Gorman
N
N
Sinclair
P R
PR
Sinclair
J F
JF
Nebert
D W
DW
De Matteis
F
F
D000818:Animals; D001663:Bilirubin / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007505:Iron-Dextran Complex / Q000494:pharmacology; D007565:Jaundice / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D013723:Teratogens / Q000633:toxicity
D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; D007505:Iron-Dextran Complex; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D001663:Bilirubin; C028451:3,4,3',4'-tetrachlorobiphenyl