Spectral interactions of tetrachlorobiphenyls with hepatic microsomal cytochrome p450 enzymes.
This study investigated the spectral interactions of hepatic microsomal cytochrome p450 (CYP) enzymes with four symmetrical polychlorinated biphenyls (PCBs): 2,2',4,4'-tetrachlorobiphenyl (PCB 47); 2,2',5,5'-tetrachlorobiphenyl (PCB 52); 2,2',6,6'-tetrachlorobiphenyl (PCB 54); and 3,3',4,4'-tetrachlorobiphenyl (PCB 77). The PCBs were selected to explore structure-activity relationships and the effect of the chlorination pattern on PCB-CYP spectral interactions. To examine CYP enzyme specificity, difference spectra were measured with hepatic microsomes prepared from control, phenobarbital (PB)-, 3-methylcholanthrene (MC)-, and dexamethasone (DEX)-treated rats in the absence and presence of CYP-specific antibodies. The four PCB congeners elicited a type I spectral change with all hepatic microsomal preparations. The binding efficiency of the PCBs was highest with microsomes from PB-treated rats. The largest absorbance change and highest binding efficiency were observed with PCB 54, the most non-coplanar congener tested. Antibody inhibition and CYP immunoquantitation data showed that the PCBs bind to CYP1A, CYP2B, CYP2C and CYP3A enzymes to varying degrees. For example, PCB 47, 52, and 54 bind preferentially to CYP2B and to a lesser extent to CYP3A enzymes in microsomes from PB-treated male rats; PCB 52 binds primarily to CYP3A enzymes in microsomes from DEX-treated female rats; and PCB 54 binds to CYP3A and to CYP2C enzymes in microsomes from control male rats. The study demonstrated that the extent of PCB-CYP binding interaction was dependent on the chlorination pattern of the PCB and on the relative abundance of individual CYP enzymes in hepatic microsomes.
Hrycay
Eugene G
EG
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3.
Bandiera
Stelvio M
SM
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D013053:Spectrophotometry
D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls