|Abstract or Summary
- Malonaldehyde, a three carbon dialdehyde, is one of the numerous
carbonyl compounds associated with oxidative deterioration of
food lipids. It is assumed to be formed as a product of lipid autoxidation
occurring according to the generally accepted free radical
mechanism. This compound is of great interest because of its potential
high reactivity and its wide occurrence in autoxidized lipids.
Malonaldehyde may participate in eliciting some of the adverse biological
and chemical effects of in vitro and in vivo lipid autoxidation.
In this investigation a micro 2-thiobarbituric acid analysis for
malonaldehyde in various biological materials was developed; the
acute toxicity, subacute toxicity and associated physiological responses
were determined; and the reaction of malonaldehyde with glycine
and protein was investigated.
The single oral median lethal dose (LD₅₀) of malonaldehyde administered
to rats as the ethoxy derivative, 1, 1, 3, 3-tetraethoxy propane, and the enolic sodium salt, sodium beta-oxyacrolein, was
found to be 527 mg (slope function 1.67) and 632 mg (slope function
1.23) per kg body weight respectively. The LD₅₀ of malonaldehyde
determined with sodium beta-oxyacrolein was the more accurate estimation
of its acute toxicity.
Subacute feeding of rats malonaldehyde as the ethoxy derivative,
1, 1, 3, 3-tetraethoxypropane, and as the sodium salt of the enamine
derivative of glycine, sodium N-prop-2-enal amino acetate, elicited
a series of similar varied and marked anatomical, physiological and/
or biochemical changes over control animals. Ingested malonaldehyde
was largely metabolized or altered so that it was no longer detectable
by reaction with 2-thiobarbituric acid. It was distributed
throughout the body and particularly in the blood and glandular tissue.
Dietary malonaldehyde was found to be concentrated in erythrocytes
where it had apparently reacted in vivo with the intracellular protein,
tentatively with hemoglobin. A decreased growth rate, a lowered diet
utilization, varying degrees of anemia, increased organ weights,
symptoms of various vitamin deficiencies, and abnormal nitrogen and
tryptophan metabolism were observed. Histomorphological damage
to liver tissue included a lytic necrosis of parenchymal cells, increased
parenchymal cell and nuclear size, bile ductular proliferation
with vacuolation of parenchymal cytoplasm with cyst formation.
The response to dietary malonaldehyde probably involved both a dirept toxic action at the cellular level and an interaction with some fraction(s) of the diet altering its nutrient value.
The reaction of malonaldehyde with glycine was found to yield
the enamine, N-prop-2-enal amino acetic acid. The reaction was
shown to conform to a S [subscript n] 2 mechanism. The rate of the reaction was
shown to be highly dependent on the hydrogen ion concentration. The
maximum observed reaction rate was found near pH 4.20. A postulated
mechanism for the reaction involves the nucleophilic 1, 4-addition
of the amino nitrogen of glycine to the end carbon atom of the alpha,
beta-unsaturated carbonyl system of the enol of malonaldehyde.
The reaction of malonaldehyde with bovine plasma albumin was
shown to involve the e-amino lysine and N-terminal amino aspartic
acid functions as judged by their loss to reaction with 1-fluoro-2, 4-
dinitrobenzene. The rate of the reaction was dependent on the hydrogen
ion concentration with a maximum observed reaction rate near
pH 4.30. Malonaldehyde did not appear to participate in an intermolecular
cross-linking reaction as judged by the lack of viscometric
hardening of gelatin sols. Presumptive evidence for the reaction
of malonaldehyde, derived from autoxidized lipids, and the ε-amino
lysine functions of bovine plasma albumin was obtained. A postulated
mechanism for the reaction of malonaldehyde with protein involves
the nucleophilic 1,4-addition of the free amino functions on the protein
to the end carbon atom of the alpha, beta-unsaturated carbonyl
system of the free enol to form an enamine linkage.