[Metabolism of 2,2',4,5,5'-pentachlorobiphenyl (CB101) by liver microsomes of rats, hamsters and guinea pigs].
Our previous studies have shown that six metabolites, namely 3-hydroxy (OH)-, 3'OH-, 4'-OH-, 3',4'-dihydroxy (diOH)-, 3'-methylsulfone (CH3SO2)- and 4'-CH3SO2-2,2',4,5,5'-pentachlorobiphenyl (CB101), were found in the serum and liver of rats, hamsters and guinea pigs 4 days after administration of CB101. In this study, the in vitro metabolism of CB101 was studied using liver microsomes of rats, hamsters and guinea pigs, and the effect of cytochrome P450 inducers, phenobarbital (PB) and 3-methylcholanthrene (MC) on CB101 metabolism was also compared. 3-OH-, 3'-OH-, 4'-OH- and 3',4'-diOH-CB101 were formed by liver microsomes of rats, hamsters and guinea pigs except that 3-OH-CB101 was not formed by hamster liver microsomes. In untreated animals, both 3'-OH- and 4'-OH-CB101 were major metabolites. By treatment of PB, 3'-OH-CB101 was increased remarkably to 140-fold of untreated in rats and to 79-fold of untreated in hamsters, and was also increased slightly to 4-fold of untreated in guinea pigs. Moreover, PB-treatment showed a significant increase of 3', 4'-diOH-CB101 in rats and hamsters. In contrast, MC-treatment increased 4'-OH-CB101 to 2.0-, 9.6- and 3.4-fold of untreated animals in rats, hamsters and guinea pigs, respectively. In all animal species, the formation of 3',4'-diOH-CB101 from 3'-OH- and 4'-OH-CB101 proceeded at much higher rate than that from CB101 and was accelerated by PB-treatment. Only in hamster, MC-treatment decreased 3',4'-diOH-CB101 from 3'-OH- and 4'-OH-CB101 to less than 50% of untreated. Addition of 5 mM reduced glutathione suppressed the formation of 4'-OH-CB101 to 43% of control by liver microsomes of MC-treated hamsters, suggesting that 4'-OH-CB101 can be formed mainly via 3',4'-epoxide from CB101. These results indicate that the metabolism of CB101 to 3',4'-diOH-CB101 is principally catalyzed by CYP2B enzymes, which prefer 4'-OH- and 3'-OH-CB101 to CB101.
Ohta
Chiho
C
Faculty of Nutritional Sciences, Nakamura Gakuen University, 5-7-1, Befu, Johnan-ku, Fukuoka 814-0198, Japan.
Matsuoka
Mikiko
M
Haraguchi
Koichi
K
Kato
Yoshihisa
Y
Endo
Tetsuya
T
Koga
Nobuyuki
N
D000818:Animals; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D051381:Rats
D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010634:Phenobarbital