Sepsis是一种病理性状，会影响给药药物的代谢，导致它们预期功效的持续时间和强度发生变化。促炎细胞因子可以下调细胞色素P450（P450s）的表达。使用兴奋炎性反应物质如脂多糖已经研究了炎性情况下P450表达的影响，但是很少有研究专注于临床脓毒症模型。在这里，我们展示盲肠结扎穿孔（CLP）是一种研究人类多微生物脓毒症的方法，会导致IL-1β，IL-6和肿瘤坏死因子α（TNFα）的表达在CLP手术后24小时出现。在CLP操作后，IL-6-/-小鼠的生存率明显低于WT小鼠。此外，CLP导致Cyp2c29和Cyp3a11基因在IL-1α-/-/β-/-（IL-1-/-）和TNFα-/-小鼠以及WT小鼠中表达显著下调。相反，CLP对IL-6-/-小鼠的Cyp3a11表达没有显著影响。尽管CLP降低了IL-6-/-小鼠中Cyp2c29的表达水平，但CLP操作的WT小鼠中Cyp2c29的表达低于CLP操作的IL-6-/-小鼠。由于IL-6耗竭，CLP诱导的脓毒症导致对应P450蛋白水平和活性的下降在mRNA表达水平上被废除。因此，CLP诱导的脓毒症下调P450基因表达，特别是Cyp2c表达，这种效应与IL-6有关，而不影响对抗CLP诱导的脓毒症。这些发现展示了CLP在研究P450的调节方面的有用性，并突显IL-6作为脓毒症下药物代谢能力的潜在指标。版权所有©2023 Elsevier B.V.。

Sepsis is a pathological condition that affects the metabolism of administered drugs, leading to changes in the duration and intensity of their intended efficacies. Proinflammatory cytokines downregulate the expression of cytochrome P450s (P450s). The effects of P450 expression under inflammatory conditions have been studied using prophlogistic substances such as lipopolysaccharide; however, few studies have focused on clinical models of sepsis. Here, we show that cecal ligation and puncture (CLP), an approach for the study of human polymicrobial sepsis, leads to the expression of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα) at 24 h after the CLP operation. Following CLP, IL-6-/- mice exhibited markedly lower survival than WT mice. In addition, CLP led to the significant downregulation of Cyp2c29 and Cyp3a11 gene expression in IL-1α-/-/β-/- (IL-1-/-) and TNFα-/- mice as well as in WT mice. In contrast, CLP elicited no significant effect on Cyp3a11 expression in IL-6-/- mice. Although CLP reduced the Cyp2c29 expression level in IL-6-/- mice, the expression of Cyp2c29 was lower in CLP-operated WT mice than in CLP-operated IL-6-/- mice. The reduction in the respective P450 protein levels and activities due to CLP-induced sepsis, reflected in the mRNA expression levels, was abolished by IL-6 depletion. Thus, CLP-induced sepsis downregulates P450 gene expression, particularly Cyp2c expression, and this effect is associated with IL-6 without affecting resistance to CLP-induced sepsis. These findings demonstrate the usefulness of CLP for studying the regulation of P450s and highlight IL-6 as a potential indicator of drug-metabolizing capacity under septic conditions.Copyright © 2023 Elsevier B.V. All rights reserved.