Deciphering the metabolism and interaction between natural and synthetic agents
Nutraceutical byproducts: The consumption of a wide range of substances in nature have
potent impacts on human physiology, ranging from beneficial to addictive and/or highly toxic. Several natural products or analogs derived from them are beneficial pharmaceuticals. And there are a host of natural products marketed as neutraceutical supplements that are widely used but have not been subjected to the same exhaustive and very expensive evaluation as pharmaceuticals. Although "natural" does not mean safe, it is widely implied.
Even where the primary metabolism of a natural agent has been reported, published studies have rarely dug deeper into the metabolism and potential effects of the metabolite(s) of a given substance (1). Many natural substances are initially metabolized by gut microflora-the byproducts of which may provide the primary physiological response, be inactive and/or impact the metabolism of prescription pharmaceuticals.
The CypExpress™ P450 expression system has been used in multiple recent studies in efforts to bridge the gaps in understanding of natural product metabolites, including their potential impact on the metabolism and function of ethical pharmaceuticals. Poor and colleagues have applied CypExpress™ systems to evaluate the metabolism and potential interactions with pharmaceuticals of several natural flavonoids and their sulfate and glucuronide byproducts produced by gut microflora (2-9).
Toxins and opiods: In separate studies, the same group has applied CypExpress™ enzymes to further characterize the metabolism of several mycotoxins and their potential impact on the metabolism of pharmaceuticals (10,11). The contributions of individual P450 enzymes to the metabolism of fentanyl and some analogs, as well as naloxone and related opioid antagonists, has also been investigated using CypExpress™ (12).
Pharmaceuticals: Although as widely used as "traditional" P450 expression systems, CypExpress™ has been reported as an excellent system for assessing the pharmacokinetics of sulfonylated Phe(3-Am)-derived inhibitors type II transmembrane serine proteases (13). It has also been used to investigate the interaction of MI-1851, a substrate-analog furin inhibitor that has significant SARS-CoV-2 antiviral activity, with human P450 enzymes (14).
Steroid Metabolism: CypExpress™ has also proven useful for advancing our understanding of endogenous substances. Barnard, et. al. used CypExpress™ Aromatase to dig deeper into the metabolism of 11-ketotestosterone into estrogens (15).
References:
1. Paine, Mary F. "Natural products: Experimental approaches to elucidate disposition mechanisms and predict pharmacokinetic drug interactions." Drug Metabolism and Disposition 48.10 (2020): 956-962.
2. Poór, Miklós, et al. "Interactions of resveratrol and its metabolites (resveratrol-3-sulfate, resveratrol-3-glucuronide, and dihydroresveratrol) with serum albumin, cytochrome P450 enzymes, and OATP transporters." Biomedicine & Pharmacotherapy 151 (2022): 113136.
3. Mohos, Violetta, et al. "Testing the pharmacokinetic interactions of 24 colonic flavonoid metabolites with human serum albumin and cytochrome P450 enzymes." Biomolecules10.3 (2020): 409.
4. Mohos, Violetta, et al. "Inhibitory effects of quercetin and its main methyl, sulfate, and glucuronic acid conjugates on cytochrome P450 enzymes, and on OATP, BCRP and MRP2 transporters." Nutrients 12.8 (2020): 2306.
5. Kaci, Hana, et al. "Interaction of luteolin, naringenin, and their sulfate and glucuronide conjugates with human serum albumin, cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) enzymes and organic anion transporting polypeptide (OATP1B1 and OATP281) transporters." Biomedicine & Pharmacotherapу 157 (2023): 114078.
6. Faisal, Zelma, et al. "Interaction of silymarin components and their sulfate metabolites with human serum albumin and cytochrome P450 (2C9, 2019, 2D6, and 3A4) enzymes." Biomedicine & Pharmacotherapy 138 (2021): 111459.
7. Fliszár-Nyúl, Eszter, et al. "Inhibitory effects of polyphenols and their colonic metabolites on CYP2D6 enzyme using two different substrates." Biomedicine & Pharmacotherapy 131 (2020): 110732.
8. Fliszár-Nyúl, Eszter, et al. "Interactions of 7, 8-dihydroxyflavone with serum albumin as well as with CYP2C9, CYP2C19, CYP3A4, and xanthine oxidase biotransformation enzymes." Biomolecules 9.11 (2019): 655.
9. Mohos, Violetta, et al. "Effects of chrysin and its major conjugated metabolites chrysin-7-sulfate and chrysin-7-glucuronide on cytochrome P450 enzymes and on OATP, P-gp, BCRP, and MRP2 transporters." Drug Metabolism and Disposition 48.10 (2020): 1064-1073.
10. Kaci, Hana, et al. "Interaction of mycotoxins zearalenone, a-zearalenol, and ẞ-zearalenol with cytochrome P450 (CYP1A2, 2C9, 2C19, 2D6, and 3A4) enzymes and organic anion