Genetic vitamin B6 deficiency exacerbates alcohol behavioral responses, metabolism, and toxicity in Drosophila

Alcohol abuse is a leading cause of preventable deaths. Alcohol affects brain function and metabolism, including GABA transmission and vitamin B6 (VB6) levels. VB6 is a cofactor for GABA synthesis and degradation; however, the interaction between VB6 deficiency and alcohol consumption remains unknown. We utilized dietary VB6 manipulations and Drosophila models with mutations in pyridox(am)ine-5'-phosphate oxidase (PNPO), a key enzyme in converting dietary VB6 to active VB6, to examine this. Our findings demonstrate that PNPO deficiency reduces alcohol aversion and increases alcohol consumption, whereas alcohol consumption worsens VB6 deficiency, suggesting a vicious cycle. Biochemically, PNPO deficiency and alcohol exposure converge on amino acid metabolism, altering levels of inhibitory neurotransmitters GABA and glycine. Moreover, PNPO deficiency and alcohol exposure synergistically lead to lethality, which can be rescued by low dose but not high dose VB6 supplementation. These results highlight the significance of VB6 in public health, especially in alcohol use and alcohol toxicity.