Exploring the Role of CYP3A4 Mediated Drug Metabolism in the Pharmacological Modulation of Nitric Oxide Production

Abstract

Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation, and cytochrome P450, the major enzymes involved in drug metabolism, share striking similarities. Therefore, it makes sense that cytochrome P450 drug mediated biotransformations might play an important role in the pharmacological modulation of nitric oxide synthase. In this work, we have undertaken an integrated in vitro assessment of the hepatic metabolism and nitric oxide modulation of previously described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess the implication of CYP450 activities over production of nitric oxide. In vitro systems based in human liver microsomes and activated mouse macrophages were developed for these purposes. Additionally in vitro production the hepatic metabolites of dual inhibitor, roxithromycin, was investigated achieving the identification and isolation of main hepatic biotransformation products. Our results suggested that for some macrolide compounds, the cytochrome P450 3A4 derived drug metabolites have an important effect on nitric oxide production and might critically contribute to the pharmacological immunomodulatory activity observed.

Clinical Perspective of FDA Approved Drugs With P-Glycoprotein Inhibition Activities for Potential Cancer Therapeutics

“…The FDA approved macrolide antibiotics (erythromycin, azithromycin, and clarithromycin) were all reported as p-gp inhibitors. This has been supported by many studies in the literature (64)(65)(66). Macrolides are well known CYP3A4 inducers (67,68), thus it may interfere with pharmacokinetics with various results, since CYP3A4 and p-gp would both play a role in drug-drug interaction.…”

“…This has been supported by many studies in the literature ( 64 – 66 ). Macrolides are well known CYP3A4 inducers ( 67 , 68 ), thus it may interfere with pharmacokinetics with various results, since CYP3A4 and p-gp would both play a role in drug-drug interaction. Indeed, investigations regarding macrolides upon anticancer drugs have been made to further clarify whether efficacious drug effect can be adequately delivered ( 69 ).…”

Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A

“…Experimental procedure was described before. 55 Assessment of CYP450 inhibition was conducted in 96-well plate format at 37 °C. Test compounds were dissolved in DMSO/acetonitrile (ACN) (2 μL) and diluted in 98 μL of NADPH solution (2 mM).…”

“…Experimental procedure was described before 55 . Assessment of CYP450 inhibition was conducted in 96-well plate format at 37 °C.…”

Monooxygenase System and NO Metabolism in Liver Microsomes of Rats with Toxic Hepatitis and the Effect of Sesquiterpene Lactones

“…Toxic liver damage caused by various xenobiotics is accompanied by activation of free radical processes by metabolites of the damaging agent, which leads to destruction of endoplasmic reticulum membranes and dysfunction of membrane-bound enzymes, including the cytochrome P-450 system [1]. Cytochrome P-450 activity largely depends on the functioning of NO synthases, a component of the NOergic system [8,9] that is activated as a part of the cell's defense mechanism in diseases of the immune system, impaired liver detoxification function, and endogenous intoxication [7], which leads to enhanced production of NO and damage to nuclear and mitochondrial DNA, proteins, and lipids of cell membranes, inhibition of ATP synthesis and electron transport in mitochondria followed by the development of endotoxemia [5].…”