Brain glutathione as a target for aetiological factors in neurolathyrism and konzo.

Both neurolathyrism and konzo are associated with the nutritional dependence of human populations on a single plant food. These diseases express themselves as chronic disorders of upper motor neurones, leading to signs and symptoms that characterise amyotrophic lateral sclerosis (motor neurone disease). The plant food associated with neurolathyrism is grass pea, which contains the neurotoxic ß-N-oxalyl-α,ß-diaminopropionic acid (ß-ODAP). The plant food associated with konzo is cassava, which may contain significant concentrations of cyanogenic glycosides and their degradation products. A monotonous diet of grass pea is likely to generate nutritional deficiencies; it is proposed that one of these, plasma methionine deficiency, may predispose neurones to the neurotoxic effects of ß-ODAP. Subjects suffering from konzo also have low concentrations of plasma methionine as a result of a dietary deficiency of this amino acid. However, the plasma cystine concentration is also compromised because cyanide released from cyanogenic glycosides in cassava probably reacts with plasma cystine non-enzymatically. The product of this reaction is 2-imino-4-thiazolidine carboxylic acid. Since both plasma methionine and cystine are used for glutathione synthesis it seems likely that one common feature that leads to motor neurone death in neurolathyrism and konzo is the depletion of glutathione in the central nervous system.

An intermediary role for the tremorgenic mycotoxin TR-2 in the biosynthesis of verruculogen.

14C-Labelled compound TR-2, a tremorgenic mycotoxin, was administered to Penicillium raistrickii in submerged fermentation. Half of the added radiolabel was taken up by the fungus during the 60 h incubation period and the secondary metabolites subsequently isolated, principally verruculogen but also fumitremorgin B, were found to be radiolabelled. The efficiency of biosynthetic incorporation of TR-2 into verruculogen within the mycelium was at least 35%, demonstrating for the first time an intermediary role for TR-2. Fumitremorgin B was also TR-2-derived but may not be an important intermediate in verruculogen biosynthesis.

Biosynthesis of penitrems and roquefortine by Penicillium crustosum.

Roquefortine and the penitrems were biosynthesised concurrently at an approximately equimolar rate by Penicillium crustosum after growth and sporulation. [14C]mevalonic acid was incorporated (15% efficiency) into the isoprenoid regions of the penitrem and roquefortine molecules to an extent consistent with their 6:1 molar ratio of isoprenoid components. [14C]penitrem A (specific activity, 3.4 X 10(2) mu Ci mmol-1) and 14C-penitrems B, C, and E readministered to young cultures were metabolically interconverted, indicating considerable metabolic flux, though generally directed towards penitrem A as the end product and suggesting a metabolic grid for the penitrem metabolites. Addition of bromide to the medium preferentially favored the production of bromo-analogs rather than the usual chloropenitrems.

Metabolism and excretion of [14C] verruculogen in a sheep.

[14C] Verruculogen (75 micrograms/kg) was given intravenously to a sheep under barbiturate anaesthesia to prevent the severe tremor and convulsions which would otherwise have occurred. Two hours later 28 per cent of the tremorgenic mycotoxin was detected in the liver, bile and small intestine. Approximately 0.5 per cent was excreted in the urine. Trace amounts of radiolabel were detected in the cortex and corpus striatum of the brain. Verruculogen was metabolised by the liver and converted completely to four more polar products, including two isomeric forms of desoxy-verruculogen and the weakly tremorgenic mycotoxin TR-2. The principal and most polar metabolite excreted is probably an isomer of TR-2.

Metabolism of verruculogen in rats.

Radiolabeled verruculogen was detected in a wide range of body tissues 6 min after intravenous administration, but after a further 20 min it was mainly being excreted via the biliary route. In isolated liver perfusion, [14C]verruculogen was rapidly taken up by the liver and metabolized completely, principally to the related tremorgen TR-2 but also to a desoxy derivative of verruculogen. In addition, a smaller amount of an isomer of TR-2 was detected. These metabolic products were excreted in the bile.