Role of retinal metabolism in methanol‐induced retinal toxicity

Abstract

Methanol is a toxicant that causes systemic and ocular toxicity after acute exposure. The folate-reduced (FR) rat is an excellent animal model that mimics characteristic human methanol toxic responses. The present study examines the role of the methanol metabolites formaldehyde and formate in the initiation of methanol-induced retinal toxicity. After a single oral dose of 3.0 g/kg methanol, blood methanol concentrations were not significantly different in FR rats compared with folate-sufficient (FS) (control) rats. However, FR rats treated with 3.0 g/kg methanol displayed elevated blood (14.6 mM) and vitreous humor (19.5 mM) formate levels and abnormal electroretinograms (loss of b-wave) 48 h postdose. FR rats pretreated with disulfiram (DSF) prior to 3.0 g/kg methanol treatment failed to display these symptoms. Formaldehyde was not detected in blood or vitreous humor with or without DSF treatment, suggesting that formate is the toxic metabolite in methanol-induced retinal toxicity. Additionally, creating a blood formate profile (14.2 mM at 48 h) similar to that observed in methanol-treated rats by iv infusion of pH-buffered formate does not alter the electroretinogram as is observed with methanol treatment. These data suggest that intraretinal metabolism of methanol is necessary for the formate-mediated initiation of methanol-induced retinal toxicity.

Folate and Folate-Dependent Enzymes Associated with Rat CNS Development

“…Recent reports [Martinasevic et al, 1996;Neymeyer et al, 1997] dealing with 10-FTHFDH expression in the mature rat and human CNS showed that glia, especially astrocytes, strongly express 10-FTHFDH. It is well recognized that glia are critical for neuronal homeostasis, for the process of neuronal cell migration and for neuronal protection from certain neurotoxins [Lee et al, 1994;Del Bigio, 1995;Garner et al, 1995]. We suggest that 10-FTHFDH and folate play a role in these glial functions.…”

“…In methanol poisoning of primates, formate is the major toxic metabolite leading to retinal and optic nerve toxicity [Hayreh et al, 1977]. Although untreated rats do not show symptoms of intoxication following the administration of formate-producing precursors such as methanol, folate-deficient or nitrousoxide-treated rats (which are depleted in tetrahydrofolate) do exhibit characteristic signs of methanol poisoning such as metabolic acidosis and ocular dysfunction [Garner et al, 1995;Eells, 1990]. To date, no assessment of frank CNS toxicity has been made, especially during the period of early postnatal development.…”

Ocular Changes after Intravitreal Injection of Methanol, Formaldehyde, or Formate in Rabbits

“…Not all methanol is necessarily metabolized in the liver. Metabolism of methanol in the rat retina has been suggested (Garner et al 1995). Moore & Lee (1987) reported that methanol was metabolised to formaldehyde by azide-sensitive catalase in the eye.…”

“…did not alter the electroretinogram (Garner et al 1995). Furthermore, a trace of formaldehyde was found in the vitreous of a methanol-poisoned patient (Benton & Calhaun 1952).…”

Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells

“…Methanol is oxidized by alcohol dehydrogenase to produce formaldehyde, which is further oxidized to formic acid by formaldehyde dehydrogenase. Metabolism of methanol to formaldehyde via peroxisomal enzymes has been demonstrated in rat retina in vitro [19], and the presence of cytoplasmic aldehyde dehydrogenase activity has been demonstrated in several regions of the rat and mouse eye, including the retina [20,21]. Susceptibility to methanol toxicity is dependent upon the relative rate of formate clearance.…”