Possible Interaction: Ethanol and Tretinoin

“There is extensive biochemical and enzymatic overlap between ethanol clearance and retinoic acid biosynthesis.”

“At the cellular level, ethanol appears to inhibit Sonic hedgehog signalling, alter levels of retionoic acid activity , trigger a Ca(2+)-CamKII-dependent pathway that antagonises WNT signalling, affect cytoskeletal dynamics and increase oxidative stress.”

“Specifically, interference of alcohol with retinoids and cofactors of transmethylation processes are outlined.”

“While the precise biochemical mechanisms governing alcohol’s effect remain to be elucidated, its profound effect on hepatic retinoid status is irrefutable.”

“Despite this realization, insight into whether interactions between ethanol and retinoids represent cause versus effect requires additional research.”

“ Ethanol affects many aspects of retinoid metabolism and mechanisms of action site specifically, but no robust data support inhibition of vitamin A metabolism, resulting in decreased atRA in vivo during normal vitamin A nutriture.”

“A new study, using assays that are highly sensitive for endogenous atRA, has reported that ethanol toxicity in mice actually increased atRA concentration in certain tissues, including brain hippocampus, apparently due to a mobilization of hepatic retinyl esters that led to increased retinol and atRA in specific tissues.”

“However, previous work, using very high exogenous doses of retinol, found that ethanol toxicity led to decreased formation of atRA , apparently due to competitive inhibition of alcohol dehydrogenase, which is purportedly involved in the conversion of retinol to retinal.”

“ Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism.”

“In brief, ethanol interferes with retinoid metabolism and its signaling, induces the release of fibrogenic cytokines such as transforming growth factor beta-1 (TGFbeta-1) from HSCs, up-regulates the gene expression of collagen I and enhances type I collagen protein production by HSCs.”

“Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism.”

“However, if the K(m) for ethanol were smaller, as for human ADH4, the rate of retinol oxidation and formation of retinoic acid would be significantly decreased during metabolism of 50 mM ethanol.”

“Simulations of the oxidation of retinol to retinoic acid with mouse ADH4 and human aldehyde dehydrogenase (ALDH1), using rate constants estimated for all steps in the mechanism, suggest that ethanol (50 mM) would modestly decrease production of retinoic acid.”