Celery extract inhibits mouse CYP2A5 and human CYP2A6 activities via different mechanisms

Abstract

Abstract. Human cytochrome P450 (CYP) 2A6 participates in the metabolism of nicotine and precarcinogens, thus the deliberate inhibition of CYP2A6 may reduce cigarette consumption and therefore reduce the risk of developing the types of cancer associated with smoking. The inhibitory effects and mechanisms of celery (Apium graveolens) extract on mouse CYP2A5 and human CYP2A6 activity remain unclear. These effects were investigated in mouse and human liver microsomes using coumarin 7-hydroxylation in a probe reaction. Celery extract reduced CYP2A5 and CYP2A6 activities in vitro in a dose-dependent manner. In vivo experiments also showed that celery extract markedly decreased CYP2A5 activity. The inhibition of celery extract on CYP2A5 was time-and nicotinamide adenine dinucleotide phosphate (NADPH)-independent, and was markedly reduced by ultracentrifugation. Additionally, the inhibition of celery extract on CYP2A6 was time and NADPH-dependent. Levels of inhibition were characterized by a K i , the measure of the tightness of bonds between the enzyme and its inhibitor, of 266.4 µg/ml for CYP2A5, and a K i of 1,018 µg/ml and K inact of 0.3/min for CYP2A6. K inact is the maximal rate of enzyme inactivation at a saturating concentration of inhibitor. The coumarin derivative 5-methoxypsoralen present in celery extract did not solely to the inhibition of CYP2A5/6 activity. In conclusion, celery extract inhibited the levels of mouse CYP2A5 and human CYP2A6 activity via different mechanisms: Mixed competitive inhibition for CYP2A5 and mechanism-based inhibition for CYP2A6.

The Effectiveness of Dietary Byproduct Antioxidants on Induced CYP Genes Expression and Histological Alteration in Piglets Liver and Kidney Fed with Aflatoxin B1 and Ochratoxin A

“…CYP2E1 , like other xenobiotic-metabolizing P450s, is mainly located in the membrane of the ER and can be induced under a variety of metabolic or nutritional conditions [ 89 ]. The regulation of the CYP2E1 gene in the E1 group was probably due to the hydroxylation of coumarin-derived compounds that were catalyzed by CYP2A enzymes, which are considered to be specific indicators for the presence of CYP2 enzymes [ 94 ], with the p-coumaric acid being present in grapeseed and sea buckthorn byproducts.…”

Effect of celery (Apium graveolens) seed extract on hypertension: A randomized, triple‐blind, placebo‐controlled, cross‐over, clinical trial

“…The combination might be beneficial for the treatment of HTN, as celery causes an increase in the plasma level of captopril, which can enhance its efficacy. In a study by Deng, Pu, Wang, and Yu (2016), celery extract inhibited the levels of mouse CYP2A5 and human CYP2A6 activity via different mechanisms. Thus, celery can reduce the metabolism of other drugs and increase their blood concentration.…”

Cancer Hazard Identification Integrating Human Variability: The Case of Coumarin

“…151,152 Celery extract has been shown to irreversibly inhibit the coumarin 7-hydroxylation activity of human CYP2A6. 153 Phenethyl isothiocyanate, a constituent of cruciferous vegetables, competitively inhibited coumarin 7-hydroxylase activity with a Ki value of 18.2 ± 2.5 µM. 154 Additionally, diallyl disulfide, an organosulfuric compound present in garlic oil, has been shown to be a potent inhibitor of CYP2A6.…”