Bilirubin and uroporphyrinogen oxidation by induced cytochrome P4501A and cytochrome P4502B. Role of polyhalogenated biphenyls of different configuration.
In previous work it was shown that hepatic microsomes from rats treated with 3-methylcholanthrene and similar inducers had increased bilirubin-degrading activity. The activity was further stimulated by addition of 3,4-tetrachlorobiphenyl (TCB), a response specifically dependent on CYP1A1. Here, we compared the effect of adding PCBs of either planar or non-planar configuration on rate of bilirubin degradation, monooxygenase activity and NADPH/O(2) consumption by liver microsomes from animals treated with either phenobarbital or 3-methylcholanthrene/beta-naphthoflavone. We also examined the oxidation of uroporphyrinogen (hexahydro-uroporphyrin) (URO'gen) under these conditions. Polychlorinated biphenyl (PCBs) stimulated the rate of bilirubin and URO'gen oxidation with microsomes expressing high levels of either CYP2B or CYP1A, inhibiting at the same time their monooxygenase activities (PROD and EROD, respectively); however, non-planar di-ortho-substituted PCBs were preferentially active with phenobarbitone-induced microsomes, in contrast to those active with 3-methylcholanthrene/beta-naphthoflavone microsomes, where a planar configuration was required for activity. An antibody raised against CYP2B1 markedly inhibited the PCB-dependent bilirubin degradation and PROD activities of phenobarbital-induced microsomes with similar dose-response curves for the two effects. Increased microsomal utilizations of NADPH and O(2) were also caused by PCBs with both types of induced microsomes and here again PCBs of different configuration were preferentially active. It is concluded that PCBs of the appropriate configuration may interact with either CYP1A1 or CYP2B1, increase production of oxidative species by an uncoupling mechanism, and lead to oxidation of target molecules in the cell, among these uroporphyrinogen and bilirubin.
De Matteis
Francesco
F
Department of Pharmacology, University of Turin Medical School, Via P. Giuria 13, I-10125, Turin, Italy. francesco.dematteis@unito.it
Dawson
Sally J
SJ
Pons
Nicoletta
N
Pipino
Sandra
S
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001189:Aryl Hydrocarbon Hydroxylases; D001663:Bilirubin / Q000737:chemistry / Q000378:metabolism*; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008968:Molecular Conformation; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014577:Uroporphyrinogens / Q000737:chemistry / Q000378:metabolism*
D000906:Antibodies; D014577:Uroporphyrinogens; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D001663:Bilirubin; D010100:Oxygen; D010634:Phenobarbital