Borrego-Ruiz Alejandro, Borrego Juan J
Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain.
Departamento de Microbiología, Universidad de Málaga, 29071 Málaga, Spain.
Genes (Basel). 2025 Mar 30;16(4):403. doi: 10.3390/genes16040403.
BACKGROUND/OBJECTIVES: This review examines the role of pharmacogenomics in individual responses to the pharmacotherapy of various drugs of abuse, including alcohol, cocaine, and opioids, to identify genetic variants that contribute to variability in substance use disorder treatment outcomes. In addition, it explores the pharmacomicrobiomic aspects of substance use, highlighting the impact of the gut microbiome on bioavailability, drug metabolism, pharmacodynamics, and pharmacokinetics.
Research on pharmacogenetics has identified several promising genetic variants that may contribute to the individual variability in responses to existing pharmacotherapies for substance addiction. However, the interpretation of these findings remains limited. It is estimated that genetic factors may account for 20-95% of the variability in individual drug responses. Therefore, genetic factors alone cannot fully explain the differences in drug responses, and factors such as gut microbiome diversity may also play a significant role. Drug microbial biotransformation is produced by microbial exoenzymes that convert low molecular weight organic compounds into analogous compounds by oxidation, reduction, hydrolysis, condensation, isomerization, unsaturation, or by the introduction of heteroatoms. Despite significant advances in pharmacomicrobiomics, challenges persist including the lack of standardized methodologies, inter-individual variability, limited understanding of drug biotransformation mechanisms, and the need for large-scale validation studies to develop microbiota-based biomarkers for clinical use.
Progress in the pharmacogenomics of substance use disorders has provided biological insights into the pharmacological needs associated with common genetic variants in drug-metabolizing enzymes. The gut microbiome and its metabolites play a pivotal role in various stages of drug addiction including seeking, reward, and biotransformation. Therefore, integrating pharmacogenomics with pharmacomicrobiomics will form a crucial foundation for significant advances in precision and personalized medicine.
背景/目的：本综述探讨了药物基因组学在个体对各种滥用药物（包括酒精、可卡因和阿片类药物）药物治疗反应中的作用，以确定导致物质使用障碍治疗结果差异的基因变异。此外，还探讨了物质使用的药物微生物组学方面，强调了肠道微生物群对生物利用度、药物代谢、药效学和药代动力学的影响。
药物遗传学研究已经确定了几个有前景的基因变异，这些变异可能导致个体对现有物质成瘾药物治疗反应的差异。然而，这些发现的解释仍然有限。据估计，遗传因素可能占个体药物反应差异的20%-95%。因此，仅遗传因素不能完全解释药物反应的差异，肠道微生物群多样性等因素也可能起重要作用。药物微生物生物转化是由微生物外酶产生的，这些酶通过氧化、还原、水解、缩合、异构化、不饱和化或引入杂原子将低分子量有机化合物转化为类似化合物。尽管药物微生物组学取得了重大进展，但挑战依然存在，包括缺乏标准化方法、个体间差异、对药物生物转化机制的了解有限，以及需要大规模验证研究来开发基于微生物群的生物标志物用于临床。
物质使用障碍药物基因组学的进展为与药物代谢酶常见基因变异相关的药理学需求提供了生物学见解。肠道微生物群及其代谢产物在药物成瘾的各个阶段（包括寻求、奖赏和生物转化）中起关键作用。因此，将药物基因组学与药物微生物组学相结合将为精准和个性化医学的重大进展奠定关键基础。
