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ABSTRACT:This article describes an in vitro investigation of the inhibition of cytochrome P450 (P450) 2C9 by a series of flavonoids made up of flavones (flavone, 6-hydroxyflavone, 7-hydroxyflavone, chrysin, baicalein, apigenin, luteolin, scutellarein, and wogonin) and flavonols (galangin, fisetin, kaempferol, morin, and quercetin). With the exception of flavone, all flavonoids were shown to inhibit CYP2C9-mediated diclofenac 4-hydroxylation in the CYP2C9 RECO system, with K i value <2.2 M. In terms of the mechanism of inhibition, 6-hydroxyflavone was found to be a noncompetitive inhibitor of CYP2C9, whereas the other flavonoids were competitive inhibitors. Computer docking simulation and constructed mutants substituted at residue 100 of CYP2C9.1 indicate that the noncompetitive binding site of 6-hydroxyflavone lies beside Phe100, similar to the reported allosteric binding site of warfarin. The other flavonoids exert competitive inhibition through interaction with the substrate binding site of CYP2C9 accessed by flurbiprofen. These results suggest flavonoids can participate in interactions with drugs that act as substrates for CYP2C9 and provide a possible molecular basis for understanding cooperativity in human P450-mediated drug-drug interactions.Flavonoids are polyphenolic secondary metabolites that are widely distributed in higher plants and ingested by humans in their regular food (Kuhnau, 1976;Bravo, 1998). Flavones and flavonols are two major classes of flavonoids (Table 1). Flavonols are present in a variety of fruits and vegetables, whereas flavones are mainly found in cereals and herbs (Hertog et al., 1993;Bravo, 1998;Peterson and Dwyer, 1998). In the West, the estimated daily intake of both flavonols and flavones is in the range 20 to 50 mg per day (Cermak and Wolffram, 2006). However, given the growing demand for food supplements or herbal remedies containing flavonoids, and given that in some countries flavonoids are commonly used as therapeutic agents (2008 State Food and Drug Administration RPC, http://app1.sfda.gov. cn/datasearch/face3/dir.html), it is likely that some individuals are exposed to relatively high levels of flavonoids. This points to a need for more information on the safety and potential toxicity of flavonoids.In the early 1980s, several studies reported the effects of flavonoids on the activity of hepatic cytochrome P450 (P450) enzymes (Buening et al., 1981;Lasker et al., 1982). Since then, the ability of flavonoids to inhibit isoforms of CYP450, particularly CYP1A1 and CYP1A2, has been extensively confirmed (Cermak and Wolffram, 2006). Several clinical studies have reported that some flavonoids have the capacity to alter drug metabolism in vivo (Peng et al., 2003;Rajnarayana et al., 2003;Choi et al., 2004). However, for CYP2C9, which ranks among the most important drug-metabolizing enzymes in humans and hydroxylates 10 to 20% of commonly prescribed drugs (Kirchheiner and Brockmöller, 2005), only two flavones, luteolin and baicalein, and one flavonol, quercetin, have been found to ...

This study suggests that this novel CYP2C9 allele was correlated with reduced plasma clearance of drugs that are substrates for CYP2C9.

P oor outcomes have been reported recently in patients with pneumonia associated with coronavirus disease 2019 (COVID-19) and cardiac injury. 1-3 These reports did not characterize patients as dead or discharged from hospital because the COVID-19 pandemic had not completed its course at the time of reporting. 1-3 The initial findings suggested that patients admitted to the intensive care unit (ICU) had an arrhythmia burden of 44.4%; 4 however, the exact nature of these arrhythmias was not characterized. Knowing now that cardiac injury is an important predictor of death, characterizing arrhythmias and determining independent predictors of outcome may allow health care providers to implement aggressive therapy and assign accurate probabilities for the outcome, which can be used to identify high-risk groups. In addition, such data would assist in decisions on discharge from the emergency department, therapy with QT-prolonging drugs, rhythm monitoring and triage of ventilators and ICU beds. 5 In Wuhan, China, the initial outbreak of COVID-19 has run its full course, which provides an opportunity to characterize outcomes and inform strategy for Europe and North America. As such, we evaluated 170 patients from Wuhan who had cardiac injury that was diagnosed early during their admission for pneumonia associated with COVID-19 for the outcomes of death, discharge and arrhythmias. We also characterized the effect of QT-prolonging drugs in these patients. We determined independent predictors of death and mechanical ventilation in this population with cardiac injury and severe COVID-19. Methods Study participants, setting and design Infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was diagnosed using contact history, clinical symptoms and a positive result for SARS-CoV-2 using nucleotide polymerase