Metabolism of dichlorobiphenyls by highly purified isozymes of rat liver cytochrome P-450

Ls, Kaminsky; Mw, Kennedy; Sm, Adams; Fp, Guengerich

doi:10.1021/bi00529a009

Cited by 113 publications

(80 citation statements)

References 35 publications

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“…PB is metabolized by enzymes it induces, including P450s, and the sleeping time of rats decreases after a few days of continuous treatment. ␤NF-inducible rat P450 1A1 uses ␤NF as a substrate (Vyas et al, 1983), and some of the polychlorinated biphenyls in Aroclor are also substrates for the PB-and ␤NF-inducible P450s (Kaminsky et al, 1981). CCl 4 -induced isoprostane production is exacerbated by treatment of rats with INH or PB (Morrow et al, 1992), but this is a rather extreme case in that the only product is a reactive radical itself (⅐CCl 3 ).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Oxidative Damage in Rats Is Associated with Barbiturate Response but Not Other Cytochrome P450 Inducers

Dostálek¹,

Brooks²,

Hardy³

et al. 2007

Mol Pharmacol

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Previously published studies have shown that cytochrome P450 (P450) enzyme systems can produce reactive oxygen species and suggest roles of P450s in oxidative stress. However, most of the studies have been done in vitro, and the potential link between P450 induction and in vivo oxidative damage has not been rigorously explored with validated biomarkers. Male Sprague-Dawley rats were pretreated with typical P450 inducers (␤-naphthoflavone, phenobarbital (PB), Aroclor 1254, isoniazid, pregnenolone 16␣-carbonitrile, and clofibrate) or the general P450 inhibitor 1-aminobenztriazole; induction of P4501A, -2B, -2E, -3A, and -4A subfamily enzymes was confirmed by immunoblotting and the suppression of P450 by 1-aminobenztriazole using spectral analysis. PB and Aroclor 1254 significantly enhanced malondialdehyde and H 2 O 2 generation and NADPH oxidation in vitro and significantly enhanced formation in vivo, in both liver and plasma. Some of the other treatments changed in vitro parameters but none did in vivo. The PB-mediated increases in liver and plasma F 2 -isoprostanes could be ablated by 1-aminobenztriazole, implicating the PB-induced P450(s) in the F 2 -isoprostane elevation. The markers of in vivo oxidative stress were influenced mainly by PB and Aroclor 1254, indicative of an oxidative damage response only to barbiturate-type induction and probably related to 2B subfamily enzymes. These studies define the contribution of P450s to oxidative stress in vivo, in that the phenomenon is relatively restricted and most P450s do not contribute substantially.

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Section: Discussionmentioning

confidence: 99%

In Vivo Oxidative Damage in Rats Is Associated with Barbiturate Response but Not Other Cytochrome P450 Inducers

Dostálek¹,

Brooks²,

Hardy³

et al. 2007

Mol Pharmacol

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“…There have been studies of the isoform-specific biotransformation of PCB congeners, particularly by the major Phenobarbital-inducible CYP2B isoforms and 3-methylcholanthrene-inducible CYP1A isoforms, e.g. (Kaminsky et al, 1981). Human CYP2B6 and rat CYP2B1 were the major isoforms for metabolism of PCB153 (Duignan et al, 1987;Ariyoshi et al, 1992), shown in figure 1, although it should be noted that PCB153 is relatively resistant to metabolism, and is therefore one of the more biologically persistent PCB congeners (Letcher et al, 2000).…”

Section: Formation and Properties Of Polychlorobiphenylols (Oh-pcbs)mentioning

confidence: 99%

Effects of food natural products on the biotransformation of PCBs

James

Sacco

Faux

2008

Environmental Toxicology and Pharmacology

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Many food products, particularly fruits and vegetables, contain natural products that affect biotransformation enzymes. These may be expected to affect the rate of biotransformation of PCBs that are metabolized by the affected enzymes. The first step in PCB metabolism is cytochrome P450-dependent monooxygenation. Natural products present in cruciferous vegetables have been shown to selectively up-regulate CYP1A1 and CYP1A2 isozymes on chronic ingestion, and may lead to increased metabolism of those PCB congeners that are substrates for the induced P450s. On the other hand, several natural products selectively inhibit monooxygenation, especially in the intestine, and may lead to increased bioavailability and reduced metabolism of dietary PCBs. Food natural products are known to affect phase II pathways important in the detoxication of hydroxylated PCBs, namely UDP-glucuronosyltransferase and PAPS-sulfotransferase. Continual dietary exposure to chrysin and quercetin, found in fruits and vegetables, induces UGT1A1 and may reduce exposure to hydroxylated PCBs through increased glucuronidation. These and other natural products are also inhibitors of glucuronidation and sulfonation, potentially leading to transient decreases in the elimination of hydroxylated PCBs. In summary, the expected effects of food natural products on PCB biotransformation are complex and may be biphasic, with initial inhibition followed by enhanced biotransformation through monooxygenation and conjugation pathways.

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“…Although oxidative metabolism of PCBs by rats has been studied extensively (Kato et al, 1980;Kaminsky et al, 1981), there has been only limited comparative analysis of in vivo metabolism of PCBs between hamsters and guinea pigs (Koga and Yoshimura, 1996). The results of the present study indicated that the tissue distribution profiles of PCB residues and OH-and MeSO 2 -CBs were largely dependent on the chlorination patterns classified into four groups.…”

Section: Discussionmentioning

confidence: 99%

Comparative Metabolism of Polychlorinated Biphenyls and Tissue Distribution of Persistent Metabolites in Rats, Hamsters, and Guinea Pigs

Haraguchi

Koga²,

Kato³

2004

Drug Metab Dispos

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ABSTRACT:The present study was performed to compare the metabolite profiles of polychlorinated biphenyls (PCBs) in the liver and serum of rats, hamsters, and guinea pigs after exposure to a PCB mixture, Kanechlor 500 (100 mg/kg, i.p.). The percentage of contribution of major PCB residues in the liver 5 days after exposure indicated that nonplanar PCBs with 2,4-or 2,3,4-chlorine substitution were more abundant in the liver in the order rats (43% of total PCBs) > hamsters (20%) > guinea pigs (11%), whereas coplanar PCBs with 4-, 3,4-, or 3,4,5-chlorine substitution were predominant in guinea pigs (61%), followed by hamsters and rats (both 26%). The hepatic concentrations of methylsulfonyl metabolites (MeSO 2 -CBs) were higher in the order guinea pigs > rats > hamsters. Whereas hamsters formed minute amounts of MeSO 2 -CBs from 2,5-dichlorosubstituted PCBs, guinea pigs formed higher levels of metaMeSO 2 -CBs derived from 2,3,6-trichloro-substituted PCBs. In contrast, the serum concentrations of phenolic PCBs were higher in the order hamsters > rats > guinea pigs. Metabolites were predominated by 4-OH-2,3,5,3,4-pentaCB (89% contribution) for rats, 3-OH-2,4,5,2,4-pentaCB (56%) for guinea pigs, and dihydroxylated metabolites (39%) for hamsters. The reduced elimination of coplanar PCBs and the specific distribution of MeSO 2 -and phenolic PCBs may have implications for the differences in sensitivity to PCB toxicity among rats, guinea pigs, and hamsters.

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Metabolism of dichlorobiphenyls by highly purified isozymes of rat liver cytochrome P-450

Cited by 113 publications

References 35 publications

In Vivo Oxidative Damage in Rats Is Associated with Barbiturate Response but Not Other Cytochrome P450 Inducers

In Vivo Oxidative Damage in Rats Is Associated with Barbiturate Response but Not Other Cytochrome P450 Inducers

Effects of food natural products on the biotransformation of PCBs

Comparative Metabolism of Polychlorinated Biphenyls and Tissue Distribution of Persistent Metabolites in Rats, Hamsters, and Guinea Pigs

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