Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies.
Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies.
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DOI：
10.1111/jphp.12812
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Greenblatt DJ
中科院分区：
文献类型：
--
作者：
Cao L;Kwara A;Greenblatt DJ
过度暴露于对乙酰氨基酚（APAP，扑热息痛）可通过形成消耗肝脏谷胱甘肽的反应性代谢物并导致肝细胞氧化应激和损伤而导致肝损伤。该代谢产物的生成由细胞色素P450（CYP）亚型介导，主要是CYP 2 E1。许多天然存在的黄酮类化合物可以减轻实验动物模型中APAP诱导的肝毒性。我们的目标是确定这些保护作用的机制，并评估可能的人类适用性。两种黄酮类化合物，毛地黄黄酮和槲皮素，被评估为潜在的抑制剂的8个人类β-葡萄糖醛酸异构体，六UDP-葡萄糖醛酸转移酶（UGT）异构体，和APAP葡萄糖醛酸化和硫酸化。实验模型是基于人肝微粒体的体外代谢，使用亚型特异性底物。木犀草素和槲皮素在不同程度上抑制人类CYP 1A 2和2C 8亚型，其中对CYP 1A 2和2C 8的抑制作用最强。然而，50%抑制浓度（IC 50值）通常在微摩尔范围内。UGT亚型受到最低程度的抑制。木樨草素和槲皮素均抑制APAP硫酸化，但不抑制葡萄糖醛酸化。木樨草素和槲皮素对人体前列腺素活性的抑制作用，其IC 50值超过了这些化合物在可耐受补充剂量下的人体暴露量。研究结果表明，木犀草素和槲皮素不太可能是预防或治疗APAP诱导的肝毒性的临床价值。
Excessive exposure to acetaminophen (APAP, paracetamol) can cause liver injury through formation of a reactive metabolite that depletes hepatic glutathione and causes hepatocellular oxidative stress and damage. Generation of this metabolite is mediated by Cytochrome-P450 (CYP) isoforms, mainly CYP2E1. A number of naturally-occurring flavonoids can mitigate APAP-induced hepatotoxicity in experimental animal models. Our objective was to determine the mechanism of these protective effects, and to evaluate possible human applicability. Two flavonoids, luteolin and quercetin, were evaluated as potential inhibitors of eight human CYP isoforms, of six UDP-glucuronosyltransferase (UGT) isoforms, and of APAP glucuronidation and sulfation. The experimental model was based on in vitro metabolism by human liver microsomes, using isoform-specific substrates. Luteolin and quercetin inhibited human CYP isoforms to varying degrees, with greatest potency toward CYP1A2 and 2C8. However 50 % inhibitory concentrations (IC50 values) were generally in the micromolar range. UGT isoforms were minimally inhibited. Both luteolin and quercetin inhibited APAP sulfation but not glucuronidation. Inhibition of human CYP activity by luteolin and quercetin occurred with IC50 values exceeding customary in vivo human exposure with tolerable supplemental doses of these compounds. The findings indicate that luteolin and quercetin are not likely to be of clinical value for preventing or treating APAP-induced hepatotoxicity.
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影响因子：
4.3
作者：
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