Accumulation properties of polychlorinated biphenyl congeners in Yusho patients and prediction of their cytochrome P450-dependent metabolism by in silico analysis

Abstract

In what has become known as the Yusho incident, thousands of people in western Japan were poisoned by the accidental ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds. In this study, we investigated the accumulation patterns of 69 PCB congeners in the blood of Yusho patients in comparison with those of non-exposed controls. The blood samples were collected at medical check-ups in 2004 and 2005. To compare the patterns of PCB congeners, we calculated the concentration ratio of each congener relative to the 2,2',4,4',5,5'-hexaCB (CB153) concentration. The concentration ratios of tetra- and penta-chlorinated congeners in the blood of Yusho patients were significantly lower than those of controls. To examine the cytochrome P450 (CYP)-dependent metabolic potential of the 2,3',4,4'5-pentaCB (CB118), CB153, and 2,3,3',4,4'5-hexaCB (CB156) congeners, we conducted PCB-CYP (CYP1A1, CYP1A2, CYP2A6, and CYP2B6) docking simulation by in silico analysis. The docking models showed that human CYP1A1, CYP2A6, and CYP2B6 isozymes have the potential to metabolize CB118 and CB153. On the other hand, it was inferred that CB156 is difficult to be metabolized by these four CYP isozymes. These results indicate that CYP1 and CYP2 isozymes may be involved in the characteristic accumulation patterns of PCB congeners in the blood of Yusho patients.

Effects of quercetin on Aroclor 1254-induced expression of CYP450 and cytokines in pregnant rats

“…In healthy hosts, agents in the PCB family are metabolized primarily in the liver through the activities of various types of cytochrome P 450 (CYP 450 ) (Zhu and Silverman 2008;Mise et al 2016). Of all the isozymes, CYP1 and CYP2 are the major forms involved in PCB metabolism (Hirakawa et al 2018). Because of this, CYP1A1 is often used a biomarker of host exposure to certain persistent organic pollutants (POP) (Foltz et al 2014;Wimmerov a et al 2016).…”

Persistent Organic Pollutants in Human Breast Milk and Associations with Maternal Thyroid Hormone Homeostasis

“…Dl-PCBs and dioxins may upregulate UDPGTs by binding with aryl hydrocarbon receptor, leading to enhanced excretion of T 4 . Non-dl-PCBs, however, may interfere with the activities of CYP enzymes (i.e., CYP 2B1 and CYP 3A1) which may also reduce circulating T 4 . , A substantial body of animal and epidemiologic studies have reported decreased THs with increasing exposure of PCBs, despite the literature being inconsistent. ,− Langer et al reported negative associations of FT 4 and TT 3 with PCBs at low exposure levels (serum level: <530 ng/g lw), but positive relations at higher levels . A recent study also observed inverse associations between low-dose PCBs and TT 3 , free T 3 , and FT 4 in a Chinese population .…”

“…Non-dl-PCBs, however, may interfere with the activities of CYP enzymes (i.e., CYP 2B1 and CYP 3A1) which may also reduce circulating T 4 . 54,55 A substantial body of animal and epidemiologic studies have reported decreased THs with increasing exposure of PCBs, despite the literature being inconsistent. 18,56−58 Langer et al reported negative associations of FT 4 and TT 3 with PCBs at low exposure levels (serum level: <530 ng/g lw), but positive relations at higher levels.…”

Aryl Hydrocarbon Receptor and Dioxin-Related Health Hazards—Lessons from Yusho

“…Dioxins and PCBs in the body are gradually and slowly metabolized by CYP1A1, CYP1A2, and CYP1B1 via an AHR-mediated process. However, the affinity of xenobiotic enzymes for these different congeners varies [ 202 ]. They are also slowly excreted from the body via sebum, sputum, and feces.…”