Coordinación Académica Región Altiplano, Universidad Autónoma de San Luis Potosí, Matehuala 78700, Mexico.
Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Durango 34120, Mexico.
Int J Environ Res Public Health. 2023 Jan 20;20(3):1901. doi: 10.3390/ijerph20031901.
Arsenic (As) is a common contaminant in drinking water in northeastern Mexico, which reduces the expression of cytochrome P450 (CYP 450). This enzyme group metabolizes numerous drugs, such as oral antidiabetic drugs such as pioglitazone (61% CYP 3A4, 49% CYP 2C8). When CYP 450's function is inadequate, it has decreased therapeutic activity in type 2 diabetes mellitus (T2DM). This study aimed to establish the effect of As on pioglitazone metabolism in patients with T2DM.
Urine, water, and plasma samples from a healthy population ( = 11) and a population with T2DM ( = 20) were obtained. Samples were analyzed by fluorescence spectroscopy/hydride generation (As) and HPLC (pioglitazone). Additionally, CYP 3A4 and CYP 2C8 were studied by density functional theory (DFT).
The healthy and T2DM groups were exposed via drinking water to >0.010 ppm, Ka values with a factor of 4.7 higher, Cl 1.42 lower, and ABCt 1.26 times higher concerning the healthy group. In silico analysis (DFT) of CYP 3A4 and CYP 2C8 isoforms showed the substitution of the iron atom by As in the active sites of the enzymes.
The results indicate that the substitution of Fe for As modifies the enzymatic function of CYP 3A4 and CYP 2C8 isoforms, altering the metabolic process of CYP 2D6 and CYP 3A4 in patients with T2DM. Consequently, the variation in metabolism alters the bioavailability of pioglitazone and the expected final effect.
确定砷（As）对 2 型糖尿病（T2DM）患者吡格列酮代谢的影响。
收集健康人群（n=11）和 T2DM 人群（n=20）的尿液、水和血浆样本。采用荧光光谱/氢化物发生法（As）和 HPLC 法（吡格列酮）对样本进行分析。此外，还通过密度泛函理论（DFT）研究了 CYP3A4 和 CYP2C8。
健康组和 T2DM 组通过饮用水暴露于 >0.010 ppm 的 As，Ka 值高 4.7 倍，Cl 值低 1.42，ABCt 值高 1.26 倍。CYP3A4 和 CYP2C8 同工型的计算（DFT）表明，酶活性部位的铁原子被 As 取代。
这些结果表明，Fe 被 As 取代改变了 CYP3A4 和 CYP2C8 同工型的酶功能，改变了 T2DM 患者 CYP2D6 和 CYP3A4 的代谢过程。因此，代谢的变化改变了吡格列酮的生物利用度和预期的最终效果。
