The metabolism of 20-hydroxyecdysone in mice: relevance to pharmacological effects and gene switch applications of ecdysteroids.

Ecdysteroids exert many pharmacological effects in mammals (including humans), most of which appear beneficial, but their mechanism of action is far from understood. Whether they act directly and/or after the formation of metabolites is still an open question. The need to investigate this question has gained extra impetus because of the recent development of ecdysteroid-based gene-therapy systems for mammals. In order to investigate the metabolic fate of ecdysteroids in mice, [1α,2α-(3)H]20-hydroxyecdysone was prepared and injected intraperitoneally to mice. Their excretory products (urine+faeces) were collected and the different tritiated metabolites were isolated and identified. The pattern of ecdysteroid metabolites is very complex, but no conjugates were found, in contrast to the classical fate of the (less polar) endogenous vertebrate steroid hormones. Primary reactions involve dehydroxylation at C-14 and side-chain cleavage between C-20 and C-22, thereby yielding 14-deoxy-20-hydroxyecdysone, poststerone and 14-deoxypoststerone. These metabolites then undergo several reactions of reduction involving, in particular, the 6-keto-group. A novel major metabolite has been identified as 2ß,3ß,6α,22R,25-pentahydroxy-5ß-cholest-8(14)-ene. The formation of this and the other major metabolites is discussed in relation to the various effects of ecdysteroids already demonstrated on vertebrates.

Iridoids with anti-inflammatory activity from Vitex peduncularis.

A new iridoid, pedunculariside, together with the known iridoid agnuside were isolated from the butanol extract of Vitex peduncularis stem bark. Both pedunculariside and agnuside showed preferential inhibition of COX-2, with IC50 values of 0.15 +/- 0.21 mg/ml and 0.026 +/- 0.015 mg/ml respectively, while having only small inhibitory effects on COX-1. Both compounds did not exhibit cytotoxicity against vero cells.

Highly oxygenated ecdysteroids from Vitex canescens root bark.

Highly oxygenated ecdysteroids, (24R)-11 alpha, 20,24-trihydroxyecdysone and 11 alpha,20,26-trihydroxyecdysone, have been isolated from the polar fraction of Vitex canescens root bark. The latter exists as two C-25 epimers which could be separated by reversed-phase HPLC.

Choleretic activity of phloracetophenone in rats: structure-function studies using acetophenone analogues.

The relationship between the chemical structure and choleretic activity of phloracetophenone (2,4,6-trihydroxyacetophenone) was investigated in adult male rats. Fourteen acetophenone analogues, with different substituents on the benzene nucleus, were intraduodenally administered and bile samples were collected via a bile fistula. All of the compounds tested immediately induced choleresis. For the same number of substituents on the benzene ring, hydroxy analogues induced a greater choleresis. The number and position of hydroxy substituents on the benzene nucleus play an important role in determining choleretic activity and biliary secretion of bile acid, but had no relation to biliary excretion of cholesterol. The choleretic activity of the hydroxylated compounds was inversely related to hydrophobicity, as inferred by thin-layer chromatography (TLC). Among the hydroxylated acetophenone analogues, 2,4,6-trihydroxyacetophenone was identified as the most potent, with a choleretic activity of 231.8+/-6.1 microl/mmol/min. It induced both a high bile flow rate and a high bile salt output and led to lower plasma cholesterol levels. This bile had a low lithogenic potential. The results suggest that a structural requirement for high choleretic activity of 2,4,6-trihydroxyacetophenone is a substituent hydroxy group at 4-position. Additional hydroxy groups at 2- and 6-positions are essential for the induction of higher an output of bile acid, and possibly, other solid materials.

Reduction of plasma cholesterol by Curcuma comosa extract in hypercholesterolaemic hamsters.

The influence of the extract of Curcuma comosa Roxb. (Zingiberaceae) on lipid metabolism was investigated in hypercholesterolaemic hamsters. Intragastric administration of the ethyl acetate extract of C. comosa rhizome (0-500 mg/kg per day) to hypercholesterolaemic animals for 7 days decreased both plasma triglyceride and cholesterol levels in a dose-dependent manner. The reduction of plasma cholesterol levels was accompanied by a significant increase in the hepatic cholesterol content while the triglyceride content was not significantly changed. The increase of the hepatic cholesterol content was brought about by an expansion of the free cholesterol pool which specifically augments biliary cholesterol excretion. The C. comosa extract also increased plasma high density lipoprotein (HDL)-cholesterol and decreased plasma low density lipoprotein (LDL)-cholesterol. These results suggest that the C. comosa extract exerts a hypolipidaemic action by acceleration of lipid mobilization from extrahepatic tissue to the liver which subsequently increases excretion of cholesterol via the bile for excretion.

Hypolipidemic effect of Curcuma comosa in mice.

The hypolipidemic effect of an ethyl acetate extract of the rhizome of Curcuma comosa Roxb was investigated in mice. Intragastric administration of the extract significantly decreased plasma lipid levels of both triglyceride and cholesterol but increased liver triglyceride content. Liver weight and plasma activities of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were not affected by a single administration. Prolonged treatment did not further decrease plasma lipid level but caused further increases in liver triglyceride content and weight. The lower plasma cholesterol activity of C. comose extract was found to be essentially associated with elevation of plasma HDL cholesterol level, increased excretion of fecal cholesterol and bile salt. The increase persisted throughout the period of treatment. These results suggest that C. comosa has hypolipidemic action. It exerts hypocholesterolemic activity by accelerating mobilization of cholesterol from peripheral tissues into liver and enhancing excretion of cholesterol and bile salt into feces.