Santes-Palacios Rebeca, Romo-Mancillas Antonio, Camacho-Carranza Rafael, Espinosa-Aguirre Jesús Javier
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Cd. de México, México.
División de Estudios de Posgrado, Facultad de Química, Universidad Autónoma de Querétaro, Santiago de Querétaro, México.
Toxicol Lett. 2016 Sep 6;258:267-275. doi: 10.1016/j.toxlet.2016.07.023. Epub 2016 Jul 18.
Cytochrome P4501A1 is involved in the metabolism of carcinogenic polycyclic aromatic hydrocarbons; therefore, its inhibition interferes with the carcinogenesis process induced by these compounds in rats. The human and rat CYP1A1 differ by 21% in amino acid sequence, including the active site of the enzyme; this difference may be an important factor when results obtained using animal models are interpolated to humans. Based on its previously reported CYP inhibitory properties, we studied the effects of two molecules contained within grapefruit juice, naringenin and 6',7'-dihydroxybergamottin, on human and rat CYP1A1 activity. For this purpose, the kinetics of inhibition as well as computational simulations were used. Naringenin and 6',7'-dihydroxybergamottin were found to be competitive inhibitors of human and rat CYP1A1. Additionally, naringenin exerted a mixed type inhibition effect on rat CYP1A1. Computational docking showed that inhibitors might block the oxidation of 7-ethoxyresorufin by binding to the CYP1A1 active site. Our results demonstrate the differences in CYP inhibitory mechanisms for the same molecule when CYP from different species are considered.
细胞色素P4501A1参与致癌性多环芳烃的代谢；因此，对其抑制会干扰这些化合物在大鼠体内诱导的致癌过程。人类和大鼠的CYP1A1在氨基酸序列上有21%的差异，包括酶的活性位点；当将使用动物模型获得的结果推断到人类时，这种差异可能是一个重要因素。基于其先前报道的CYP抑制特性，我们研究了葡萄柚汁中含有的两种分子，柚皮素和6',7'-二羟基佛手柑素，对人类和大鼠CYP1A1活性的影响。为此，我们使用了抑制动力学以及计算模拟。发现柚皮素和6',7'-二羟基佛手柑素是人类和大鼠CYP1A1的竞争性抑制剂。此外，柚皮素对大鼠CYP1A1发挥混合型抑制作用。计算对接表明，抑制剂可能通过与CYP1A1活性位点结合来阻断7-乙氧基试卤灵的氧化。我们的结果证明，当考虑来自不同物种的CYP时，同一分子的CYP抑制机制存在差异。
