Relationships among CYP2B6 genetic variants and serum levels of multiple polychlorinated biphenyls and hydroxylated metabolites in a Japanese population

Abstract

Production of polychlorinated biphenyls (PCBs) has been banned since 2001 but health risks from exposure persist. PCBs are metabolized by cytochrome P450 enzymes, including CYP2B6. However, the link between CYP2B6 gene polymorphisms and PCB metabolisms is poorly characterized. This study investigated the relationships among serum levels of major indicator PCBs and hydroxylated PCBs (OH-PCBs), which are PCB metabolites, and polymorphisms in CYP2B6. Blood samples (n=129) were analyzed for single nucleotide polymorphisms in CYP2B6 (p.Q172H and p.K262R), and the corresponding haplotypes (*1, *4, *6) were determined. Concentrations of PCBs and OH-PCBs were determined using gas chromatography and mass spectrometer. Congener-specific variations in PCB metabolism were associated with different CYP2B6 genotypes, particularly *1/*4 (hypothesized to increased expression) and *6/*6 (hypothesized to decreased expression). For certain PCBs, the *1/*4 genotype was linked to increased metabolite-to-parent compound ratios, while *6/*6 was associated with decreased ratios, as observed for PCB146 (β = 0.192, 95% CI: [0.100, 0.283], p < 0.0001 for *1/*4; β = −0.235, 95% CI: [–0.366, –0.105], p = 0.001 for *6/*6). However, other PCBs, such as PCB170 and PCB183, exhibited opposite or more complex patterns. Our findings indicate intricate effects of CYP2B6 gene polymorphisms on PCB metabolism and highlight the potential for genotype-specific risks in PCB-related toxicity.

Environmental Implication

PCBs are persistent in the environment and human bodies and pose potential health risks. In addition to exposure sources and levels, serum levels of PCBs largely vary in population due to difference in elimination kinetics. Cytochrome P450 are considered key enzymes for PCB metabolisms. This study demonstrated that CYP2B6 variants, particularly *1/*4 (increased expression) and *6/*6 (decreased expression) are associated with different congener composition in serum. Furthermore, *1/*4 genotype was linked to increased metabolite-to-parent compound ratios for several PCBs, indicating the potentially significant role of CYP2B6 in their metabolism. This study provides the first evidence suggesting that the CYP2B6 variants in humans may contribute to population susceptibility to multiple PCB metabolites.