Nutritional Support of the Cytochrome P450 System: B Vitamins, Glutathione and Associated Micronutrients

Background and objective: The cytochrome P450 (CYP450) system is the enzyme superfamily responsible for phase I oxidative metabolism of over 70-80% of clinically used drugs, as well as essential physiological functions including steroid synthesis, vitamin D metabolism, bile acid production, and eicosanoid processing. Its catalytic activity depends on a complex network of vitamin and mineral cofactors. Malnutrition—endemic in the geriatric patient—may compromise this system at multiple levels: heme group synthesis (iron, pyridoxine/B6), electron transfer (riboflavin/B2, niacin/B3), reactive metabolite detoxification (glutathione/GSH, selenium), and maintenance of the endoplasmic reticulum redox environment (vitamins C and E). The objective of this review is to (i) establish the biochemical basis of each nutrient-CYP450 relationship, (ii) grade the available clinical evidence, and (iii) translate this knowledge into actionable recommendations for geriatric pharmacology. Methods: Critical narrative review of the scientific literature in PubMed/MEDLINE, Cochrane Library, and specialized biochemical databases (BRENDA, UniProt, PharmGKB). High-quality mechanistic studies, randomized controlled trials, and systematic reviews were prioritized. Evidence grading follows a GRADE-adapted schema (A: robust evidence; B: moderate evidence; C: limited/indirect evidence; D: preclinical or hypothetical). Time scope: 1975-2025. Main findings: Six categories of nutrient-CYP450 relationships were identified with heterogeneous evidence levels: (1) NADPH as obligate electron donor—direct and incontrovertible relationship with niacin/B3 (GRADE A); (2) FAD/FMN as prosthetic groups of NADPH-CYP450 reductase—direct relationship with riboflavin/B2 (GRADE A/B); (3) pyridoxal-5'-phosphate as cofactor of aminolevulinate synthase in heme biosynthesis—indirect but well-established relationship with B6 (GRADE B); (4) glutathione as the primary protector against CYP450-generated reactive metabolites—solid clinical evidence in acute depletion models (GRADE A) and chronic deficiency (GRADE B); (5) selenium as glutathione peroxidase cofactor (GRADE B); and (6) vitamins C/E, zinc, and magnesium as antioxidant supports of the microsomal redox environment (GRADE B-C). Clinical implications: Detection and correction of specific nutritional deficiencies—particularly frequent in institutionalized older adults—has the potential to partially restore pharmacological biotransformation capacity and reduce oxidative damage from drug metabolism. However, indiscriminate supplementation without documented deficiency lacks clinical evidence of benefit and may generate significant drug interactions. A nutritional assessment protocol oriented to CYP450 function is proposed.