Phase I uses cytochrome P450 (CYP) enzymes to transform fat-soluble toxins into reactive intermediates. Phase II conjugates those intermediates with molecules like glutathione or glucuronate, making them water-soluble and excretable. When Phase I is fast and Phase II is slow, reactive intermediates accumulate and cause oxidative damage. Genetic variants in CYP, GST, and NAT2 genes directly control the speed and efficiency of both phases.

Glutathione is the body's primary intracellular antioxidant and a critical Phase II conjugating agent — neutralizing reactive intermediates, heavy metals, and environmental toxins. GSTM1 and GSTT1 null variants, relatively common in the general population, result in complete absence of the corresponding enzymes, reducing glutathione conjugation capacity. Individuals with these null variants have measurably elevated susceptibility to toxin accumulation and oxidative stress under equivalent exposures.

Methylation conjugation — adding a methyl group to prepare toxins for excretion — is one of the Phase II detox pathways. COMT methylates catecholamines and estrogen metabolites; HNMT methylates histamine. These reactions require SAMe as the methyl donor, which depends on adequate folate and B12 through the methylation cycle. MTHFR variants that impair methylation efficiency therefore reduce toxin clearance through methylation pathways as a downstream effect.

GSTM1 and GSTT1 null variants reduce glutathione-dependent clearance of mercury, arsenic, and cadmium. NRF2 pathway variants affect the upregulation of protective antioxidant enzymes under metal exposure. MTHFR variants impair mercury clearance indirectly because methylation supports conversion of inorganic mercury to excretable forms. Individuals with combinations of these variants may have meaningfully reduced metal clearance capacity and elevated sensitivity to environmental heavy metal exposure.

Phase I requires B-vitamins (B2, B3, B12), magnesium, iron, and zinc as enzyme cofactors. Phase II needs glutathione precursors (NAC, glycine, cysteine), sulfur compounds from cruciferous vegetables, and methylation support (5-MTHF, methylcobalamin). Sulforaphane from broccoli sprouts is among the most studied inducers of Phase II enzyme activity. Your genetic detox variants determine which of these nutritional interventions are most relevant to your individual needs.