ABSTRACT
The fruit of Eugenia jambolana Lam. is very popular for its anti-diabetic property. Previous studies on the crude extract of E. jambolana (EJE) have successfully explored the scientific basis for some of its traditional medicinal uses. Considering its wide use and consumption as a seasonal fruit, the present study investigates the ability of E. jambolana to interact with cytochrome P450 enzymes. The standardized EJE was incubated with pooled human liver microsomes to assess the CYP2C9-, CYP2D6-, and CYP3A4-mediated metabolism of diclofenac, dextromethorphan, and testosterone, respectively. The metabolites formed after the enzymatic reactions were quantified by high performance liquid chromatography. EJE showed differential effect on cytochrome P450 activities with an order of inhibitory potential as CYP2C9 > CYP3A4 > CYP2D6 having IC50 of 76.69, 359.02, and 493.05 µg/mL, respectively. The selectivity of EJE for CYP2C9 rather than CYP3A4 and CYP2D6 led to perform the enzyme kinetics to explicate the mechanism underlying the inhibition of CYP2C9-mediated diclofenac 4'-hydroxylation. EJE was notably potent in inhibiting the reaction in a non-competitive manner with Ki of 84.85 ± 5.27 µg/mL. The results revealed the CYP2C9 inhibitory potential of EJE with lower Ki value suggesting that EJE should be examined for its potential pharmacokinetic and pharmacodynamic interactions when concomitantly administered with other drugs.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Microsomes, Liver/drug effects , Plant Extracts/pharmacology , Syzygium/chemistry , Chromatography, High Pressure Liquid , Ellagic Acid/analysis , Fruit/chemistry , Humans , Microsomes, Liver/enzymology , Polyphenols/analysisABSTRACT
CONTEXT: Pterocarpus marsupium (PM) (Leguminosae), Eugenia jambolana (EJ) (Myrtaceae) and Gymnema sylvestre (GS) (Asclepiadaceae) are the most important medicinal plants in the Indian system of traditional medicine for the treatment of hyperglycemia. OBJECTIVES: Dipeptidyl peptidase-4 (DPP-4) inhibitors are the emerging class of anti-diabetic agents. However, only few compounds are commercially available. Therefore, in the present study we tried to explore the naturally occurring PM, EJ and GS semi-standardized extracts for their potential DPP-4 inhibition in vitro and in vivo. MATERIALS AND METHODS: DPP-4 inhibition was evaluated by in vitro inhibitory assay, and enzyme kinetics were calculated using one-phase exponential decay equation. Glucose load (2 g/kg) was administered to control and diabetic rats 30 min following extract administration (100, 200 and 400 mg/kg) orally once, and blood samples were withdrawn at 0, 0.5, 1, 1.5, 2 and 3 h to measure plasma active glucagon-like peptide-1 (GLP-1) levels. RESULTS: PM and EJ inhibit DPP-4 potently with IC50 values of 273.73 ± 2.96 and 278.94 ± 6.73 µg/mL, respectively, compared to GS (773.22 ± 9.21 µg/mL). PM, EJ and GS exhibit long duration of action with enzyme inhibitory half-lives of 462.3, 317.2 and 153.8 min, respectively. Extracts significantly increase GLP-1 levels compared to negative control groups and peak GLP-1 level was observed at 2 h for PM and EJ, whereas for GS it was at 1.5 h DISCUSSION AND CONCLUSION: Taken together, results suggest the extracts may have potent DPP-4 inhibitory action, and their hypoglycemic action attributed through an increase in plasma active GLP-1 levels.
Subject(s)
Gymnema sylvestre/chemistry , Hypoglycemic Agents/pharmacology , Pterocarpus/chemistry , Syzygium/chemistry , Administration, Oral , Animals , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/enzymology , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/isolation & purification , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dose-Response Relationship, Drug , Glucagon-Like Peptide 1/blood , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/isolation & purification , India , Inhibitory Concentration 50 , Male , Medicine, Ayurvedic , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Plant Extracts/pharmacology , Rats , Rats, Wistar , Time FactorsABSTRACT
The suspensions of chloroform extract of leaves in 0.3% carboxy methyl cellulose (CMC) was evaluated for hepatoprotective activity in Wistar albino rats by inducing hepatic injury with d-galactosamine (400 mg/kg). The chloroform extract of Polygala arvensis at an oral dose of 200 mg/kg and 400 mg/kg exhibited a significant (P<0.001, P<0.01 and P<0.05) protection effect by normalizing the levels of aspartate amino transferase (ASAT, GOT), alanine amino transferase (ALAT, GPT), alkaline phosphatase (ALP), total bilirubin (TB), lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TGL), albumin, total protein (TP) which were significantly (P<0.001) increased in rats by treatment with 400 mg/kg i.p. of d-galactosamine. Silymarin (25 mg/kg), a known hepatoprotective drug used for comparison exhibited significant activity (P<0.001).