A molecular dynamics perspective into estrogen receptor inhibition by selective flavonoids as alternative therapeutic options.

Zearalenone is an estrogenic mycotoxin which is a common food contaminant and has been implicated in increasing the incidence of carcinogenesis and other reproductive health ailments through the estrogen receptor alpha (ERα) pathway. Competitive ERα blockers such as 4-Hydroxytamoxifen (OHT), are synthetic FDA approved drugs which, albeit being an effective anticancer agent, induces life altering side effects. For this reason, there is an increased interest in the use of naturally occurring medicinal plant products such as flavonoids. This study aimed to identity flavonoid ERα inhibitors and provide insights into the mechanism of inhibition using computational techniques. The Molecular Mechanics/Generalized Born Surface Area calculations revealed that quercetrin, hesperidin, epigallocatechin 3-gallate and kaempferol 7-O-glucoside out of 14 flavonoids had higher binding affinity for ERα than OHT. The structural analysis revealed that the binding of the compounds to the receptor lead to dynamic alterations, which induced conformational shift in the structure and orientation of the receptor resulting in stabilised, compact and low energy systems. The results of this study provide imperative information that supports the use of flavonoids in the inhibition of ERα to prevent or ameliorate the consequential adverse effects associated with zearalenone exposure.Communicated by Ramaswamy H. Sarma.

An insight on the nature of biochemical interactions between glycyrrhizin, myricetin and CYP3A4 isoform.

Drug interaction studies are imperative to gain insights into the beneficial or harmful effects of therapeutic and dietary agents. This study investigated the mechanism of modulatory roles of glycyrrhizin (GLH) and myricetin (MYC) on the human CYP3A4 isoform using in silico and in vitro methods. While MYC had concentration-dependent inhibitory effect on CYP3A4 (IC50 : 10.5 ± 0.55 µM) with characteristic Km and Vmax values of 1.13 µM and 1.54 nM/min, respectively, GLH exhibited no inhibitory effect on CYP3A4 activity in vitro. These observations are consistent with the results of in silico evaluations where the effect of MYC compared well with that of ketoconazole (a known CYP3A4 inhibitor) against CYP3A4. Overall, the established interactions between the study compounds and CYP3A4 could potentiate clinically vital drug-drug interactions and has lent credence to the mechanism of modulatory effect of MYC and GLH on CYP3A4 that could guide their safe use as therapeutic agents. PRACTICAL IMPLICATIONS: Myricetin (MYR) and glycyrrhizin (GLH) occur freely in commonly ingested foods and their supplements are recommended for the treatment of several debilitating diseases such as diabetes, cancer, and cardiovascular complications. This study provided an insight on the possible interactions that could be established between these compounds (MYR and GLH) and CYP3A4 when ingested and metabolized by the liver. The results suggested possibilities of potential clinical drug-drug interactions and advocates for their cautious use within the therapeutic dose in food supplements or medications to avoid probable liver damage.

Influence of Clerodendrum volubile leaf extract on doxorubicin-induced toxicity and inhibition of carbonyl reductase mediated metabolism.

OBJECTIVES: Doxorubicin (DOX) is a commonly used chemotherapeutic drug. However, its non-target organ toxicities pose a serious problem. This study is to assess the protective role of Clerodendrum volubile leaf extract (CVE) against DOX-induced toxicities in rats. In addition, the inhibitory activities of three phytochemical compounds (Rutin, Gallic acid and Rosmarinic acid) from CVE against Carbonyl reductase 1 (CBR1) were examined. METHODS: Rats were randomly divided into 5 groups: (a) Control group rats were given 0.9% NaCl as vehicle, (b) DOX group: A single dose of DOX (25 mg/kg; i.p.) was administered and rats were sacrificed 4 days after DOX injection, while groups (c-e) CVE-treated DOX rat groups were given 125, 250 and 500 mg/kg body weight of extracts orally for 12 consecutive days; 8 days before, and 4 days after the DOX administration. Computational techniques were used to determine the inhibitory activities of the compounds against CBR1. RESULTS: DOX intoxication caused a significant increase (p<0.05) in serum marker enzymes: ALT, AST, ALP, LDH, CK activities. The levels of liver and heart tissues antioxidant parameters: GPx, SOD, CAT, and GSH were significantly (p<0.05) decreased in DOX-intoxicated rats with concomitant elevation of malondialdehyde levels. Pretreatment with CVE reversed the above trends. From the structural analysis, Rutin and RSA exhibited the highest binding free energies against CBR1, and also exhibited structural stability when bound with CBR1. CONCLUSIONS: Our study indicates the protective effect of CVE when used in combination with doxorubicin thus improving its chemotherapeutic application via inhibition of CBR-mediated metabolism.

White butterfly (Clerodendrum volubile) leaf extract protects against carbon tetrachloride-induced hepatotoxicity in rats.

Currently, there is increasing attention towards flavonoids and phenolic compounds of plant origin because of their association with decrease in the incidence of cardiovascular diseases and different types of cancer. The present study investigates the protective effect of Clerodendrum volubile (C. volubile) methanolic extracts against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Control rats (group I) received olive oil (1 mL/kg, i.p.), group II received CCl4 in olive oil (1 ml/kg, i.p.) to induce hepatotoxicity, groups III, IV and V were pretreated with leaf extract of C. volubile at 125 mg/kg, 250 mg/kg and 500 mg/kg body weight respectively for 14 days prior to CCl4 administration, group VI received vitamin E (100 mg/kg, p.o.) as standard antioxidant to compare with antioxidant effects of the extract. CCl4 hepatotoxicity, characterized by significant (P < 0.05) increase in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), hepatic degeneration, and inflammation was attenuated by C. volubile methanolic extracts. The serum lipid parameters which include high density lipoprotein (HDL) and low density lipoprotein (LDL) were significantly (P < 0.05) decreased, and increased respectively by CCl4. Methanolic extracts of C. volubile significantly prevented the decrease in the level of HDL and the increase in LDL in a dose-dependent manner (P < 0.05). Decrease in total protein induced by CCl4 was moderately increased following administration of methanolic extracts of C. volubile. Lipid peroxidation was significantly (P < 0.05) reduced while the reduced glutathione (GSH) level and the activities of hepatic antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) were significantly elevated by C. volubile extract in the CCl4-treated rats. Our findings indicate that C. volubile extract has a significant protective effect against CCl4-induced hepatotoxicity in rats which may be due to its antioxidant properties which is comparable to the reference antioxidant, vitamin E, used in this study.