Methanol, when introduced into all mammals, is oxidized into
formaldehyde and then into
formate, mainly in the liver. Such metabolism is accompanied by the formation of
free radicals. In all animals,
methanol oxidation, which is relatively slow, proceeds via the same intermediary stages, usually in the liver, and various metabolic systems are involved in the process, depending on the animal species. In nonprimates,
methanol is oxidized by the
catalase-
peroxidase system, whereas in primates, the
alcohol dehydrogenase system takes the main role in
methanol oxidation. The first metabolite (
formaldehyde is rapidly oxidized by
formaldehyde dehydrogenase) is the
reduced glutathione (GSH)-dependent
enzyme. Generated
formic acid is metabolized into
carbon dioxide with the participation of H 4
folate and two
enzymes, 10-formyl H 4
folate synthetase and
dehydrogenase, whereas nonprimates oxidize
formate efficiently. Humans and monkeys possess low hepatic H 4
folate and 10-formyl H 4
folate dehydrogenase levels and are characterized by the accumulation of
formate after
methanol intoxication. The consequences of
methanol metabolism and toxicity distinguish the human and monkey from lower animals.
Formic acid is likely to be the cause of the
metabolic acidosis and
ocular toxicity in humans and monkeys, which is not observed in most lower animals. Nevertheless, chemically reactive
formaldehyde and
free radicals may damage most of the components of the cells of all animal species, mainly
proteins and
lipids. The modification of cell components results in changes in their functions.
Methanol intoxication provokes a decrease in the activity and concentration of
antioxidant enzymatic as well as nonenzymatic parameters, causing enhanced membrane peroxidation of
phospholipids. The modification of
protein structure by
formaldehyde as well as by
free radicals results changes in their functions, especially in the activity of
proteolytic enzymes and their inhibitors, which causes disturbances in the proteolytic-antiproteolytic balance toward the proteolytics and enhances the generation of
free radicals. Such a situation can lead to destructive processes because components of the proteolytic-antiproteolytic system during enhanced
membrane lipid peroxidation may penetrate from blood into extracellular space, and an uncontrolled proteolysis can occur. This applies particularly to
extracellular matrix proteins.