Effect of 3,3',4,4'-tetrachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl on the induction of hepatic lipid peroxidation and cytochrome P-450 associated enzyme activities in rats.
Polychlorinated biphenyls (PCBs) are environmental contaminants that have been widely used for various industrial purposes. In spite of numerous studies on PCBs, however, their mechanism of toxicity remains unknown. The role of cytochrome P-450 in PCBs induced hepatic lipid peroxidation is controversial. Therefore, the present study was undertaken to study the mechanism of action of two PCBs and their role in cytochrome P-450 induction and lipid peroxidation, determined in vivo and during the incubation of subcellular fractions. We also examined whether agonist/antagonist activities between the two PCBs were occurring. Two PCBs were studied: 3,3',4,4'-tetrachlorobiphenyl (PCB-77), a non-ortho-substituted, coplanar PCB; and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), a di-ortho-substituted, non-planar PCB. Groups of male Sprague-Dawley rats were given a single i.p. injection of one of the two PCBs (at doses of 30, 150, or 300 micromol/kg), both PCBs (at doses of 30 or 150 micromol/kg), or vehicle alone. Rats were sacrificed after 2, 6, or 24 h; or 2, 6, or 10 days. Cytochrome P-450 induction occurred as early as 2 h with PCB-77 and 24 h with PCB-153. Significant increases in thiobarbituric acid reactive substances (TBARS) content in liver tissue occurred 2, 6 and 10 days after treatment with PCB-77 and PCB-153; it was unclear whether these PCBs were synergistic in their induction of TBARS formation. Liver microsomal fractions incubated with NADPH only showed increased TBARS formation at the highest doses of PCB-77 and PCB-153 after 6 days. The results indicate that both PCBs induced cytochrome P-450 enzymes and enhanced lipid peroxidation in liver and subcellular fractions but with different potencies and onsets of action. The results also indicate a larger time difference between cytochrome P-450 induction and lipid peroxidation for PCB-77. Thus, both PCB-77 and PCB-153 are toxic to cells, but may act via different mechanisms to induce their effects.
Fadhel
Zaineb
Z
College of Pharmacy, University of Petra, Amman, Jordan.
Lu
Zijing
Z
Robertson
Larry W
LW
Glauert
Howard P
HP
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D008054:Lipid Peroxides; D017392:Thiobarbituric Acid Reactive Substances; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C028451:3,4,3',4'-tetrachlorobiphenyl; C014024:2,4,5,2',4',5'-hexachlorobiphenyl