global gene transcription in mice after exposure to ethanol and kynurenic acid

Kynurenic acid (KYNA), an unavoidable tryptophan metabolite during fermentation is naturally blended with alcohol in all alcoholic beverages. KYNA has important biological activities from protection of nerve receptors against excessive activation in the central nervous system to suppression of host inflammatory response in the immune system. While alcohol influence of gene transcription has been well studied, the combined effect of alcohol and KYNA has not. The current research has been focused on defining the synergistic effects of alcohol and KYNA on gene expression related to tryptophan metabolism and cell signaling. Adult mice were exposed to alcohol (ethanol) and/or KYNA daily for a week. Gene expression in different tissues (brain, kidney and liver) were profiled. The results indicate that while KYNA alone largely promotes, and alcohol alone mostly inhibits gene expression, alcohol and KYNA co-administration has a stronger inhibition of global gene expression. Tryptophan metabolism is severely skewed towards kynurenine pathway by decreasing tryptophan hydroxylase 2 and increasing tryptophan dioxygenase after ethanol and KYNA co-administration. Measurements of tryptophan metabolic enzymes verified the transcriptional changes of these enzymes. Furthermore, the co-administration greatly enhances the GnRH signaling pathway. These findings provide new insight into the potential impact of alcohol and KYNA on health.