Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes

Abstract

Cytochrome P450 (CYP450) enzymes are membrane-bound blood proteins that are vital to drug detoxification, cell metabolism, and homeostasis. CYP450s belonging to CYP families 1–3 are responsible for nearly 80% of oxidative metabolism and complete elimination of approximately 50% of all common clinical drugs in humans liver hepatocytes. CYP450s can affect the body’s response to drugs by altering the reaction, safety, bioavailability, and toxicity. They can also regulate metabolic organs and the body’s local action sites to produce drug resistance through altered drug metabolism. Genetic polymorphisms in the CYP gene alone do not explain ethnic and individual differences in drug efficacy in the context of complex diseases. The purpose of this review is to summarize the impact of new inflammatory-response signaling pathways on the activity and expression of CYP drug-metabolizing enzymes. Included is a summary of recent studies that have identified drugs with the potential to regulate drug-metabolizing enzyme activity. Our goal is to inspire the development of clinical drug treatment processes that consider the impact of the inflammatory environment on drug treatment, as well as provide research targets for those studying drug metabolism.

Evaluation of important human CYP450 isoforms and P‐glycoprotein phenotype changes and genotype in type 2 diabetic patients, before and after intensifying treatment regimen using Geneva cocktail

“…In many studies, IL-1β, IL-6 and TNF-α are the most important cytokines studied in inflammatory diseases; they can change the gene expression and activity of some important isoforms of cytochrome P450. 33 The present study showed significantly higher levels of inflammation in T2D patients than in the non-diabetic healthy volunteers. Other studies on animals and humans confirm this finding; therefore, T2D is considered a metabolic syndrome and a chronic inflammatory disease that can result in different effects, including changes in the activity of metabolic enzymes, especially CYP450.…”

Hydroxyurea attenuates hepatic stellate cell proliferation in vitro and liver fibrogenesis in vivo

“…It has been speculated that urease, catalase, and the monooxygenase cytochrome P‐450 metabolize hydroxyurea 20 . Catalase and cytochrome P‐450 enzymes are expressed in hepatocytes, and therefore hepatocytes might be less susceptible to hydroxyurea compared to activated hepatic stellate cells 38,39 …”

Epigenetics and endoplasmic reticulum in podocytopathy during diabetic nephropathy progression

“…Akin to TLRs, NLRs play an important role in innate immunity by triggering pro-inflammatory cascades when pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) trigger innate immunity ( 70 , 71 ). A variety of human diseases are caused by the NLRP3 inflammasome complex, including cancer, liver disease, and DKD.…”

“…First, priming by PAMP- or DAMP-induced activation of TLR signaling, resulting in NF-κB-dependent expression of NLRP3, pro-IL-1β, and pro-IL-18. Second, various cellular mechanisms, such as potassium efflux, pore-forming toxins, calcium influx, mitochondrial dysfunction, and intracellular ROS production, trigger the formation of the NLRP3 complex and activation of CASP1 ( 70 ). Nod-like receptor protein 3 (NLRP3) inflammasome activation is responsible for the accumulation of intracellular or plasma S-adenosyl-homocysteine, promoting hyperglycemia-induced podocyte injury ( 72 ).…”