Abstract
The effect of apocynin on the activity of arylamine N-acetyltransferases (NATs) in excised liver samples was examined using eighteen Sprague-Dawley rats. Three groups of six animals each were fed a normal diet alone or a treatment of 50 or 100 mg/kg/day of apocynin via gavages for eight (8) weeks. Chronic in vivo administration of apocynin led to significant (p < 0.001) reduction of in vitro liver NAT activity up to 93% as compared with untreated rats (18.80 ± 2.10 μmols p-anisidine/min/μg liver protein). In vitro exposure of untreated liver homogenates to apocynin led to a dose-dependent inhibition of NAT activity with IC50 = 0.69 ± 0.02 mM. In silico modelling of apocynin tautomers and radical species into human NAT crystal structures supported the hypothesis that thiol functionalities in NAT enzymes may be crucial in apocynin binding. The involvement of human NAT enzymes in different pathological conditions, such as cancer, has encouraged the research for selective NAT inhibitors in both humans and animal models with possible chemopreventive properties.
Highlights
Apocynin, 4-hydroxyl-3-methoxyacetophenone or acetovanillone, was originally isolated from the roots of Apocynum cannabinum L. (Apocynacaeae) and found in Picrorhiza kurroa Royle ex Benth. (Scrophulariaceae); this natural product has been traditionally used in the Aryurvedic medicine for a range of illnesses including heart and lung diseases[1]
Whilst apocynin has been shown to be an inhibitor of certain isoforms of cytochrome P450 (CYP) enzymes[19,20], its impact on other drug metabolizing enzymes has not been reported to date
We report here the first study showing the inhibitory potency of apocynin against NAT activity in rat liver both ex vivo, following treatment with apocynin, and in vitro
Summary
The effect of apocynin on the activity of arylamine N-acetyltransferases (NATs) in excised liver samples was examined using eighteen Sprague-Dawley rats. The involvement of human NAT enzymes in different pathological conditions, such as cancer, has encouraged the research for selective NAT inhibitors in both humans and animal models with possible chemopreventive properties. Since extensive studies on human NAT genotype and phenotype have revealed a close relationship between NATs and different pathological conditions, such as cancer, looking for selective inhibitors of NAT enzymes in both humans and animal models has constituted a valuable tool to develop possible chemopreventive agents[21]. We report here the first study showing the inhibitory potency of apocynin against NAT activity in rat liver both ex vivo, following treatment with apocynin, and in vitro
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