Polychlorinated biphenyls (PCBs) are persistent environmental pollutants, whose hydroxylated metabolites (OH-PCBs) accumulate in humans and may exhibit more potent effects than their parent compounds. This study investigated serum concentrations of several persistent OH-PCBs and their parent PCBs in 129 Japanese participants, with a focus on the influence of the CYP2A6*4 gene deletion variant on OH-PCB formation in PCB metabolism. Blood samples (n = 129) were genotyped for CYP2A6 (*1, *4, *7, and *9) and CYP2B6 variants. OH-PCBs and PCBs were quantified by gas chromatography-mass spectrometry. Concentrations and metabolite-to-parent ratios were compared among three CYP2A6 genotype groups (*1/*1 as wild-type, *1/*4, *4/*4; n = 49) and multiple linear regression evaluated associations between CYP2A6 genotype and OH-PCB/PCB ratios, adjusting for CYP2B6 genotype, age, and body mass index. Jonckheere-Terpstra trend test showed significant genotype-dependent decreasing trends in metabolite-to-parent ratios of four of the six OH-PCBs to their parent PCBs (3'-OH-PCB138, 4-OH-PCB146, 3-OH-PCB153, 4-OH-PCB187). In multiple linear regression, carriers of CYP2A6 *4 showed significantly lower ratios for 3-OH-PCB153 to PCB-153 (β = -0.304 per *4 allele, 95 % CI: [-0.496, -0.112], p = 0.003) and 4-OH-PCB187 to PCB-187 (β = -0.093, 95 % CI: [-0.175, -0.011], p = 0.028). No significant decreasing trends were observed for other OH-PCBs after adjustment. In conclusion, the CYP2A6*4 loss-of-function variant is associated with reduced metabolic conversion of certain PCBs to OH-PCBs, suggesting that CYP2A6 genetic variation may modulate individual susceptibility to the health risks of PCB exposure.
Insulin plays a critical role in the regulation of lipid and carbohydrate metabolism in the liver, muscle, and adipose tissue via its receptor. The root cortex of Paeonia suffruticosa (Paeoniaceae) has been used as a crude drug, Botanpi, in several formulae of traditional Japanese (Kampo) medicines, such as Hachimijiogan, to treat type 2 diabetes mellitus (DM). We previously isolated constituents from the P. suffruticosa root cortex and found that 1,2,3,4,6-pentagalloyl-β-d-glucose (β-PGG), methyl gallate, and paeonol, but not paeoniflorin, suppressed the production of the proinflammatory mediator nitric oxide in interleukin (IL)-1β-treated hepatocytes. Here, we selected three crude drugs that are often used for patients with obesity and DM (i.e., P. suffruticosa root cortex, P. lactiflora roots, and Alisma orientale roots). Among their extracts, P. suffruticosa root cortex extract and its ethyl acetate (EtOAc)-soluble fraction significantly decreased the triglyceride content in insulin-treated rat adipocytes. Additionally, β-PGG, a constituent of this fraction, efficiently reduced the triglyceride content. When the EtOAc-soluble fraction of the P. suffruticosa root cortex was administered to leptin-deficient (ob/ob) mice, a DM model, it markedly improved hepatic lipid accumulation compared with that in the non-treated mice. Furthermore, the blood glucose level and body weight of ob/ob mice administered the EtOAc-soluble fraction were significantly decreased. In hepatocytes, β-PGG reduced mRNA levels encoding glucose transporter 2, AMP-activated protein kinase, and forkhead box O1 transcription factor in the absence of IL-1β. Overall, hydrophobic constituents, including β-PGG and paeonol, may be involved in the antidiabetic effects of P. suffruticosa root cortex on ob/ob mice.
OBJECTIVES:Hachimijiogan (MIX8), a traditional herbal formulation comprising eight crude drugs, is used clinically to alleviate symptoms associated with cold conditions. Although anti-obesity effects have been suggested, the bioactive constituents and underlying mechanisms remain poorly understood. Thus, we aimed to identify the key bioactive components responsible for the anti-obesity effects of MIX8 and elucidate the underlying mechanisms. METHODS:Modified MIX8 formulations lacking processed aconite root (PAR) (MIX7) or PAR and cinnamon (MIX6) were administered to diet-induced obese C57BL/6J mice. Body weight, fat mass, insulin sensitivity, hepatic lipid accumulation, and circulating leptin levels were evaluated. To assess the underlying mechanisms, a leptin challenge test was conducted following cinnamon extract administration. KEY FINDINGS:MIX7 suppressed weight gain, adipocyte hypertrophy, systemic insulin resistance, hepatic steatosis, and hyperleptinemia. MIX6 failed to suppress weight gain, implicating cinnamon as having anti-obesity activity. Cinnamon extract enhanced the acute anorexigenic response to leptin and restored hypothalamic leptin signalling, indicating the reversal of central leptin resistance. CONCLUSIONS:Cinnamon is an essential component of MIX8 that mediates its anti-obesity effects by restoring central leptin sensitivity. The present study provides mechanistic insights into the pharmacological basis of MIX8, supporting the preventive potential of cinnamon in managing diet-induced obesity.
