Metabolic alterations induced by topical dimethylacetylenedicarboxylate

Area of Science:

• Biochemistry
• Pharmacology
• Dermatology

Background:

• Topical drug delivery and its systemic absorption are critical.
• Understanding the metabolic effects of transdermally applied compounds is essential for safety and efficacy.
• Dimethylacetylenedicarboxylate (DMAD) is a compound with potential applications requiring investigation into its tissue disposition and metabolic impact.

Purpose of the Study:

• To investigate the tissue distribution of topically applied dimethylacetylenedicarboxylate (DMAD).
• To evaluate the effects of DMAD on glucose metabolism in vivo and in vitro.
• To identify specific metabolic pathways affected by DMAD exposure.

Main Methods:

• In vivo studies using skin-grafted athymic nude mice treated with [14C]DMAD.
• In vitro studies using excised pig skin exposed to [14C]DMAD.
• Measurement of [14C]DMAD distribution in various organs.
• Assessment of [U-14C]glucose oxidation and synthesis of fatty acids and glycogen.
• Enzyme activity assays for key metabolic enzymes.

Main Results:

• [14C]DMAD rapidly penetrated skin grafts and distributed systemically, with significant concentrations found in the liver and kidneys within 24 hours.
• DMAD application markedly decreased glucose oxidation and the synthesis of fatty acids and glycogen in liver and skin grafts.
• Activities of key enzymes in glucose-6-phosphate dehydrogenase, isocitric dehydrogenase, NADP-malic dehydrogenase, and acetyl-CoA carboxylase were significantly reduced.
• Glucokinase activity remained unaffected.

Conclusions:

• DMAD demonstrates rapid and widespread tissue distribution following topical application.
• DMAD significantly disrupts glucose metabolism by inhibiting key glycogenic, lipogenic, and tricarboxylic acid cycle enzymes.
• These findings highlight the potent metabolic effects of DMAD, warranting careful consideration in its potential therapeutic or other applications.