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

Benjamin Wang; Wenqin Fu; Atsushi Ueda; Hardik Shah; Chun-Fang Wu; Wanhao Chi; Xiaoxi Zhuang

doi:10.1093/hmg/ddag032

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

Journal article

Peer reviewed

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

Benjamin Wang, Wenqin Fu, Atsushi Ueda, Hardik Shah, Chun-Fang Wu, Wanhao Chi and Xiaoxi Zhuang

Human molecular genetics, Vol.35(7), ddag032

04/15/2026

DOI: 10.1093/hmg/ddag032

PMID: 42017538

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Abstract

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.

Mutation

Alcohol Drinking - genetics

Alcohol Drinking - metabolism

Alcoholism - genetics

Alcoholism - metabolism

Animals

Behavior, Animal - drug effects

Disease Models, Animal

Drosophila - genetics

Drosophila melanogaster - genetics

Drosophila melanogaster - metabolism

Drosophila Proteins - genetics

Drosophila Proteins - metabolism

Ethanol - toxicity

gamma-Aminobutyric Acid - metabolism

Humans

Pyridoxaminephosphate Oxidase - genetics

Pyridoxaminephosphate Oxidase - metabolism

Vitamin B 6 - metabolism

Vitamin B 6 Deficiency - genetics

Vitamin B 6 Deficiency - metabolism

Details

Title: Subtitle: Genetic vitamin B6 deficiency exacerbates alcohol behavioral responses, metabolism, and toxicity in Drosophila
Creators: Benjamin Wang - University of Chicago
Wenqin Fu - University of Chicago
Atsushi Ueda - University of Iowa
Hardik Shah - University of Chicago
Chun-Fang Wu - University of Iowa
Wanhao Chi - University of Chicago
Xiaoxi Zhuang - University of Chicago
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.35(7), ddag032
DOI: 10.1093/hmg/ddag032
PMID: 42017538
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: Oxford University Press
Grant note: T32 DA043469 / NIH HHS R01 NS111122 / NIH HHS
Language: English
Date published: 04/15/2026
Academic Unit: Iowa Neuroscience Institute; Biology
Record Identifier: 9985157604702771

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