Benjamin J. Wilson

Distribution, excretion, and binding of radioactivity in the rat after intraperitoneal administration of the lung-toxic furan, [14C]4-ipomeanol

Abstract 4-Ipomeanol [1-(3-furyl)-4-hydroxypentanone] is a poisonous metabolite produced in the mold-damaged sweet potato (Ipomoea batatas). In experimental animals the compound characteristically exhibits lung toxicity, producing prominent pulmonary edema and congestion. The distribution and excretion of radioactivity in rats after administration of [14C]4-ipomeanol has been studied. The toxin was given ip at doses of 2, 10, and 30 mg/kg. Approximately half of the administered radioactivity appeared in the urine within 2 hr, with only traces occurring in the feces and expired air. The greatest tissue concentration of radioactivity occurred in the lungs. Other organs showing significant concentrations were liver, kidney, and gastrointestinal tract. The maximal accumulation of activity occurred in the tissues within 0.5–1 h. The values declined over the next 1–2 hr, then reached a plateau representing residual activity. This residual activity is particularly high in lung, liver, and kidney, and represents the toxin or its metabolite(s) which has become tightly bound to tissue macromolecules. Binding occurs maximally in lung, and therefore may indicate that the binding phenomenon is involved in the toxic mechanism of 4-ipomeanol.

Aflatrem, a tremorgenic toxin from Aspergillus flavus

Abstract The structure of aflatrem, a tremorgenic toxin from A. flavus is reported.

Effects of rubratoxin B on liver composition and metabolism in the mouse.

Abstract A single dose of rubratoxin B (0.67 mg/kg, ip) in propylene glycol caused a transient inhibition of leucine incorporation into liver proteins of 20–30 g male mice of the Swiss-Webster strain. This 12-hr suppression was followed by a stimulation of hepatic protein synthesis that persisted for 2 days after dosing. If there was any effect of the rubratoxin initially, it was partially or completely hidden by the comparable effect of the solvent. The highest doses (1.67 mg/kg and 2.67 mg/kg) caused decreases in total glycogen and protein. There was an increase after 24 hr in total liver lipids, principally in the triglycerides, at the highest dose (2.67 mg/kg) employed. Four consecutive daily ip administrations, totaling 0.67 mg/kg of rubratoxin B, resulted in a suppression of animal growth and lowering of food intake: however, liver composition was not altered significantly. No differences were detected in biochemical parameters between animals receiving rubratoxin B ip or po. Considerably greater quantities of rubratoxin B were required orally, however, to produce effects comparable to those observed following ip injection.

Enzyme inhibition and the toxic action of moniliformin and other vinylogous α-ketoacids

Abstract The inhibition of two thiamine-requiring enzymes by the potent mycotoxin, moniliformin (1-hydroxycyclobutene-3,4-dione), was investigated. Rat brain transketolase and pyruvate dehydrogenase were inhibited 25 percent by 10 −9 M moniliformin. Studies carried out to determine if moniliformin causes enzyme inhibition by reaction with thiamine were negative. Varying the hydroxycyclobutenedione structure by substitution or ring expansion resulted in loss of toxicity and inhibition.

Development of tolerance to the pulmonary toxin, 4-ipomeanol

Abstract Tolerance to the pulmonary toxin, 4-ipomeanol, administered i.p. to mice, rats, or rabbits, or given i.v. to rats, was induced rapidly by i.p. pretreatments with small doses of 4-ipomeanol itself. Tolerance was inducible to a similar extent in male or female rats. In mice, the degree of tolerance was somewhat dependent upon the particular pretreatment regimen used. Ipomeanine, a lung-toxic furan that is closely related in structure to 4-ipomeanol, showed a cross-tolerance phenomenon with 4-ipomeanol in mice, but analogs of 4-ipomeanol that did not contain a furan ring, and which were not lung-toxic, did not induce tolerance. Pretreatments of mice with 4-ipomeanol produced tolerance to another type of lung toxin, α-naphthylthiourea (ANTU), but ANTU pretreatments did not produce tolerance to 4-ipomeanol. Secondary pretreatments with CCl4 or SKF-525A modified the degree of tolerance to 4-ipomeanol in 4-ipomeanol-pretreated animals, but CCl4 pretreatment alone did not alter the lethality of 4-ipomeanol. Pretreatments of mice with phenobarbital or 3-methylcholanthrene decreased the lethality of 4-ipomeanol. However, pretreatments of mice with tolerance-inducing doses of 4-ipomeanol did not alter the hexobarbital sleeping times or the zoxazolamine paralysis times in mice, suggesting that tolerance due to phenobarbital or 3-methylcholanthrene pretreatments was by a different mechanism than that resulting from 4-ipomeanol pretreatment. The amounts of 14CO2 appearing in the expired air were the same in control and tolerant rats administered [2-14C]ethanol. On the other hand, the amounts of radiolabeled 4-ipomeanol metabolites bound covalently to the lungs were markedly lower in 4-ipomeanol pretreated rats than in control rats; this observation is consistent with previous studies indicating that potentially lethal pulmonary damage by 4-ipomeanol is caused by an alkylating metabolite. Tolerance to 4-ipomeanol apparently results from an alteration in metabolism of the compound along toxifying and/or detoxifying pathways, but further studies are needed to determine the relative importance of changes in the 2 types of pathways. The tolerance phenomenon demonstrated with 4-ipomeanol may provide a useful model for investigating tolerance mechanisms generally applicable to other lung-toxic chemical and gases.

Aflavinine, a novel indole-mevalonate metabolite from tremorgen-producing species

Abstract The structure of aflavanine, a new diterpene indole from A . flavus , is presented.

The structure of ipomeamaronol: A new toxic furanosesquiterpene from moldy sweet potatoes

Abstract The isolation and structure of a new hepatotoxic metabolite, ipomeamaronol, from mold damaged sweet potatoes ( Ipomoea batatas ) is described.

PULMONARY TOXICITY OF NATURALLY OCCURRING 3-SUBSTITUTED FURANS

I. ABSTRACT Furans of various types are frequently encountered in the environment. The naturally occurring 3-substituted furans are of special interest because of their hepatic or pulmonary toxicity for several animal species including livestock. The sweet potato is capable of producing several hepatotoxic 3-substituted furans as stress metabolites when stimulated by various exogenous agents including fungus pathogens. Fusarium solani infection results in accumulation also of three compounds with potent lung-toxic properties– 4-ipomeanol, 1-ipomeanol, and 1,4-ipomeadiol. Experiments indicate these compounds are responsible for acute bovine pulmonary emphysema (ABPE) caused by consumption of Fusarium-infected sweet potato roots. Perilia ketone, egomaketone, and isoegomaketone are closely related pulmonary toxins occurring normally in the mint plant, Perilla frutescens. These toxins are quite similar structurally to the sweet potato toxic metabolites. P. frutescens grows wild in much of the eastern United States and has been suggested as another etiological agent of ABPE. This speculation is supported by toxicity tests of perilla ketone in laboratory animals as well as in sheep and cattle. It seems probable that additional lung-toxic factors will be found in other plants grazed by livestock.

Verrucosidin, a tremorgen from Penicillium verrucosum var cyclopium

The structure of a nitrogen-free fungal neurotoxin, verrucosidin, isolated from Penicillium verrucosum var cyclopium, has been established as (1) by chemical, spectroscopic, and X-ray crystallographic methods.