Xenobiotic receptors in mediating the effect of sepsis on drug metabolism

Chuanzhu Lv; Ling Huang

doi:10.1016/j.apsb.2019.12.003

Xenobiotic receptors in mediating the effect of sepsis on drug metabolism

Acta Pharm Sin B. 2020 Jan;10(1):33-41. doi: 10.1016/j.apsb.2019.12.003. Epub 2019 Dec 16.

Authors

Chuanzhu Lv^{1

2

3

4}, Ling Huang^{5

6

4}

Affiliations

¹ Department of Emergency, Hainan Clinical Research Center for Acute and Critical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570300, China.
² Emergency and Trauma College, Hainan Medical University, Haikou 571101, China.
³ Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences, Hainan Medical University, Haikou 571101, China.
⁴ Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou 571101, China.
⁵ Research Center for Drug Safety Evaluation of Hainan Province, Hainan Medical University, Haikou 571101, China.
⁶ Hainan Province Key Laboratory for Drug Preclinical Study of Pharmacology and Toxicology Research, Hainan Medical University, Haikou 571101, China.

Abstract

Sepsis is an infection-induced systemic inflammatory syndrome. The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways. When sepsis occurs, the expression and activity of many inflammatory cytokines are markedly affected. Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes (DMEs). Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs. Xenobiotic receptors in turn may affect the clinical outcomes of sepsis. This review focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor (PXR), aryl hydrocarbon receptor (AHR), glucocorticoid receptor (GR), and constitutive androstane receptor (CAR), DMEs such as CYP1A, CYP2B6, CYP2C9, and CYP3A4, and drug transporters such as p-glycoprotein (P-gp), and multidrug resistance-associated protein (MRPs) that are affected by sepsis. Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis.

Keywords: AHR, aryl hydrocarbon receptor; AP-1, adaptor protein 1; ARNT, AHR nuclear translocator; CLP, cecum ligation and puncture; COX-2, cyclooxygenase 2; CYPs, cytochrome P450s; DMEs, drug-metabolizing enzymes; DREs, dioxin response elements; Drug metabolism; Drug transporters; Drug-metabolizing enzymes; GC, glucocorticoid; GR, glucocorticoid receptor; GREs, glucocorticoid receptor response elements; Gsts, phase II glutathione S-transferase; HSP90, heat shock protein 90; IBD, inflammatory bowel disease; IL-1β, interleukin-1β; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; Inflammatory cytokines; LPS, lipopolysaccharide; Mrp, phase III multidrug-resistant protein; NF-κB, nuclear factor-kappa B; NOS, nitric oxide synthase; NR, nuclear receptor; Oatp2, organic anion transport polypeptide 2; P-gp, p-glycoprotein; PAS, Per/ARNT/Sim; PCN, pregnenolone-16α-carbonitrile; PKC, protein kinase C; PLA2, phospholipase A2; PRRs, pattern recognition receptors; PXR, pregnane X receptor; SRC1, steroid receptor coactivator 1; STAT3, signal transducers and activators of transcription 3; Sepsis; Sult, sulfonyl transferase; TNF-α, tumor necrosis factor; Ugts, UDP-glucuronic transferase; Xenobiotic receptors.

Publication types

Review