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R J Huxtable

Publications and source records attributed to R J Huxtable.

At least 55 records · Page 3Linked to original sources
PubMed1995

The sea anemone purine, caissarone: adenosine receptor antagonism.

Caissarone, a sea anemone iminopurine, produced an increase in the twitch response of the electrically stimulated guinea-pig ileum-myenteric plexus. In the same assay, caissarone reduced the inhibitory response to the endogenous neuromodulator, adenosine, the A1 adenosine receptor agonist, R-phenylisopropyladenosine (R-PIA), and the A2 agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA) in a dose-dependent manner. Schild plot analysis of antagonism by caissarone yielded slopes of near unity, indicating that caissarone acts as a simple competitive antagonist at the adenosine receptor. The dissociation constants (KB) for caissarone ranged from 0.53 mM to 0.78 mM. In functional nicotinic receptor assays in two human cell lines, caissarone failed either to potentiate or to reduce carbamylcholine-mediated 86Rb+ efflux. Thus, the enhancing activity of caissarone on the gut could not be attributed to activity at the ganglionic nicotinic receptor. Based on structure and pharmacological activity, caissarone appears to be the first marine product described as an adenosine receptor antagonist.

Animals↗
PubMed1994

Quantitation of the hepatic release of metabolites of the pyrrolizidine alkaloid, monocrotaline.

Pyrrolizidine alkaloids such as monocrotaline are bioactivated in the liver to pneumotoxins that cause pulmonary arterial hypertension and right ventricular hypertrophy. The release of the highly reactive, alkylating pyrrole, dehydromonocrotaline, from the isolated rat liver perfused with monocrotaline has now been demonstrated and quantified, using thiopropyl Sepharose resin as a trapping agent. The isolated liver extracted 55% of the alkaloid over the course of a 1-hr perfusion with 0.5 mM monocrotaline. Of the total monocrotaline perfused, 0.4% was excreted into bile and 7.6% was detectable as pyrrolic metabolites. Of these metabolites, 156 nmol/g liver appeared in the bile as glutathionyldehydroretronecine, with the average concentration in bile being 3.53 mM. The perfusion medium at the end of the perfusion contained 113 nmol/g liver of the two pyrroles, dehydroretronecine and glutathionyldehydroretronecine. Remaining in the liver was 56 nmol/g of tissue-bound pyrroles. Over the course of a 1-hr perfusion, 88 nmol/g liver of dehydromonocrotaline was released into the perfusate, as determined by trapping with thiopropyl Sepharose, a resin that reacts only with alkylating pyrroles. This establishes that dehydromonocrotaline is released on perfusing the isolated liver with monocrotaline. The amount released under these conditions is equivalent to 1.08 +/- 0.06 mg/kg body weight, which can be compared to the intravenous dose of 4.85 mg/kg body weight of dehydromonocrotaline found by others to be a pneumotoxic dose.

Animals↗
PubMed1992

Detection of a reactive pyrrole in the hepatic metabolism of the pyrrolizidine alkaloid, monocrotaline.

Pyrrolizidine alkaloids such as monocrotaline are bioactivated in the liver, resulting in veno-occlusive disease of the liver, pulmonary arterial hypertension, and right ventricular hypertrophy. We have searched for the formation of a reactive, alkylating pyrrole intermediate in the metabolism of monocrotaline by isolated rat liver microsomes, using the sulfhydryl-containing resin, thiopropyl sepharose 6B, as a trapping agent. Control experiments show that a toxic, chemically reactive, alkylating pyrrole such as dehydromonocrotaline binds covalently to the resin via a thioether bond, but that a less toxic, poorly alkylating pyrrole, such as dehydroretronecine, does not. Isolated hepatic microsomes metabolize monocrotaline to produce a pyrrole that binds to the resin, and that can be detected by means of the Ehrlich color reagent (p-dimethylaminobenzaldehyde). The pyrrole is releasable by silver nitrate treatment, thereby establishing it to be bound via a thioether linkage. In buffered ethanolic silver nitrate the major product is 7-ethoxy-1-hydroxymethyl-6,7-dihydro-5H-pyrrolizine (O7-ethyldehydroretronecine). This establishes that the thioether linkage is at the 7-position. The same product is obtained on release of the resin-bound pyrrole formed from the reaction of dehydromonocrotaline with the resin, thereby establishing the intermediacy of dehydromonocrotaline in the metabolism of monocrotaline.

Animals↗
PubMed1992

Hepatic glutathione concentrations and the release of pyrrolic metabolites of the pyrrolizidine alkaloid, monocrotaline, from the isolated perfused liver.

We have examined the relationship between the metabolism of the pyrrolizidine alkaloid, monocrotaline, and glutathione concentration in the isolated, perfused rat liver. On perfusion of monocrotaline (300 microM) through the isolated liver, high concentrations (1.1 mM) of its metabolite glutathionyldehydroretronecine are released into bile, while much lower amounts (4.86 microM; 0.05 mumol/g liver) accumulate in the perfusate over a 1 hr perfusion period. Metabolite concentration in both the bile and perfusate increase when the level of monocrotaline perfused is increased to 900 microM. Metabolite release is also elevated in livers pretreated with phenobarbital. Monocrotaline perfusion lowered glutathione concentrations in the liver from 30 min onwards. Livers from animals treated with buthionine sulfoximine or chloroethanol showed much lower glutathione levels after 60 min perfusion. Livers from chloroethanol-treated (but not buthionine sulfoximine-treated) animals showed significantly lower release of pyrroles into the bile on perfusion with monocrotaline, but there is no effect on the rate of build-up of pyrrolic metabolites in the perfusate. We conclude that hepatic glutathione concentrations and the release of pyrrolic metabolites of monocrotaline mutually interact. Exposure of the liver to monocrotaline reduces glutathione concentrations, while marked depletion of liver glutathione concentration leads to a decrease in the release of monocrotaline metabolites.

Animals↗