Acetaldehyde is a toxic substance common to heavy drinking of alcohol and heavy smoking of cigarettes. It has been implicated thereby in diseases of the cardiovascular, respiratory, and central nervous systems. Protection against acetaldehyde toxicity (i.e. anesthesia and lethality) was studied in rats by oral intubation of test compounds 30-45 minutes prior to oral intubation of a standardized oral LD 90 dose (18 millimoles/kilogram) of acetaldehyde. Animals were monitored for anesthesia (loss of righting reflexes) and lethality for 72 hours. A total of 18 compounds was tested. L-ascorbic acid at 2 millimoles/kilogram (mM/kg) showed moderate protection against anesthesia and marked protection against lethality. Greatest protection against anesthesia and lethality was obtained at 2 m M/kg with each of the following: L-cysteine, N-acetyl-L-cysteine, thiamin-HCl, sodium metabisulfite, and L-cysteic acid. A combination of L-ascorbic acid with L-cysteine, and thiamin-HCl at reduced dose levels (2.0, 1.0 and 0.3 mM/kg, respectively) gave virtually complete protection. A detailed literature review is presented of the rationale and significance of these findings. Our findings could point the way to a possible build-up of natural protection against the chronic body insult of acetaldehyde arising from heavy drinking of alcohol and heavy smoking of cigarettes.

The ratio of toxic dose-protective dose of the fi~st two compounds warrants further study of them in combination with thiamin as possible protective agents against the chronic toxicity of acetaldehyde associated with heavy ethanol intake and heavy smoking.

Reports of the excitatory activity of free sulfhydryl groups in the brain1B2 led us to screen homocysteine and other metabolites of the methionine-cysteine p a t h~a y ,~ as well as related mercaptoacids, for behavioral and neuropharmacological effects. The purpose of this report is to document preliminary observations (some as yet unpublished) on the convulsant and lethal effects of homocysteine and certain structurally-related, aliphatic, short-chain, mercaptoacid congeners; and the protection therefrom by other compounds. MethodsMale albino rats (Charles River C D or Sprague-Dawley strains) maintained on Purina Chow, weighing 300 to 400 grams after an overnight fast (water permitted) were injected intraperitoneally (I.P.) with test compounds prepared in 0.9% saline at various dose levels. Observations were made of depressant or excitatory behavior, convulsant activity, and lethal effects; the latter in terms of number of rats showing convulsions and/or death within a given period of time out of the total number tested. For each compound at least 10 rats (and often as many as 20) were used for each dose level tested. Results and CommentsInitially, the following metabolites of the methionine-cysteine pathway were tested at a dose level of 7.4 mmoles/kg: oL-methionine, DL-homocysteine, DLhomocystine, L-serine, DL-homoserine, and L-cysteine. Only the free amino acids (not salts, pH range 5-7) were used, necessitating the injection of methionine, homocysteine, and homocystine as fine suspensions. Adjustment of amino acids to pH 6.6 f 0.3 with dilute NaOH gave essentially the same results. Of all the above amino acids tested, only homocysteine (and its thiolactone . HCI) showed convulsant activity characterized by spontaneous, tonic-clonic, grand-ma1 type seizures and "running fits." Convulsions (preceded by a depressed phase akin to somnolence) occurred within one hour and death within two hours after injection in all animals tested. Dose-response curve studies of DL-homocysteine revealed the half-maximal convulsant dose ( CD50) to be approximately 5.5 mmoles/kg. At this dose level, 18 of 33 rats (55% ) developed convulsions within 90 minutes and 5 of 33 (15%) died. No adverse reactions nor death occurred with methionine, serine, and homoserine. With cysteine, only depressed activity (no convulsions) was observed and only 1 of 15 rats (7%) died within 24 hours. Homocystine (found in homocystinuria) showed no adverse reactions; however, prolonged weight loss developed and 6 of 15 rats (40%) died within two to eight days. Prior 1.P. injection of homoserine, serine, betaine, or glycine at 14.8 mmoleslkg 30 minutes in advance protected 90% to 100% against the