Abstract
Polychlorinated dibenzo-p-dioxins (PCDDs) and coplanar polychlorinated biphenyls (PCBs) contribute to dioxin toxicity in humans and wildlife after bioaccumulation through the food chain from the environment. The authors examined human and rat cytochrome P450 (CYP)-dependent metabolism of PCDDs and PCBs. A number of human CYP isoforms belonging to the CYP1 and CYP2 families showed remarkable activities toward low-chlorinated PCDDs. In particular, human CYP1A1, CYP1A2, and CYP1B1 showed high activities toward monoCDDs, diCDDs, and triCDDs but no detectable activity toward 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD). Large amino acids located at putative substrate-recognition sites and the F-G loop in rat CYP1A1 contributed to the successful metabolism of 2,3,7,8-tetraCDD. Rat, but not human, CYP1A1 metabolized 3,3',4,4',5-pentachlorobiphenyl (CB126) to two hydroxylated metabolites. These metabolites are probably less toxic than is CB126, due to their higher solubility. Homology models of human and rat CYP1A1s and CB126 docking studies indicated that two amino acid differences in the CB126-binding cavity were important for CB126 metabolism. In this review, the importance of CYPs in the metabolism of dioxins and PCBs in mammals and the species-based differences between humans and rats are described. In addition, the authors reveal the molecular mechanism behind the binding modes of dioxins and PCBs in the heme pocket of CYPs.
Highlights
Dioxins containing polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are generated naturally through processes such as forest fires and waste incineration; dioxins are generated as byproducts of industrial processes (Figure 1)
4-OH-3,3',4',5,5'-pentaCB was produced in vitro. These results suggest that CB126 is detoxified by rat CYP1A1 because polychlorinated biphenyls (PCBs) congeners that are less chlorinated and hydroxylated generally have less hydrophobicity and decreased binding affinity for the Ah receptor that is responsible for dioxin toxicity [18]
The authors described the metabolism of PCDDs and PCBs via cytochrome P450 (CYP)-dependent hydroxylation
Summary
Dioxins containing polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are generated naturally through processes such as forest fires and waste incineration; dioxins are generated as byproducts of industrial processes (Figure 1). Hamsters, and guinea pigs treated with the CYP inducers phenobarbital (PB) and MC, 2,2',3,4',5,5',6-heptaCB (CB187) was metabolized to different hydroxylated metabolites depending on the animal species [21]. These results showed that there are species-specific differences with regard to the production of metabolites, indicating that the expression levels of CYP genes and the activities of the gene products differ among mammals. One of the advantages of the yeast expression system is that whole cells of recombinant S. cereviasiae producing human CYPs can be used as biocatalysts for the biosynthesis of metabolites This system was used to predict the metabolism of PCDDs and coplanar. The metabolites 8-OH-2,3,7-triCDD and 2-OH-1,3,7,8-tetraCDD that were detected in Victor Yushchenko were likely produced by CYPs belonging to the CYP1 family whose expression was induced by 2,3,7,8-tetraCDD (Figure 3A) [31]
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