The impact of genetic polymorphisms in xenobiotic-metabolizing enzymes and the risk of oral cancer: a critical review

Abstract Oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs) affect many individuals, where exposure to xenobiotics such as tobacco, alcohol, and betel quid is highly prevalent. Inter-individual variability plays a key role regarding genetic polymorphisms in xenobiotic‑metabolizing enzymes. In this study, we searched PubMed, Scopus and Web of Science (up to April 2026) for observational studies and meta‑analyses evaluating CYP1A1, CYP1B1, CYP2E1, GSTM1, GSTT1, GSTP1 and GSTM3 polymorphisms in OSCC and OPMDs. Twenty-one studies met the inclusion criteria. Data on exposures, genotypes and risk estimates were extracted and synthesized qualitatively. Most studies showed that GSTM1 and/or GSTT1 null genotypes are associated with increased risk of OSCC, particularly in Asian cohorts with heavy tobacco and/or betel quid exposure. CYP1A1 and CYP2E1 variants exhibited more heterogeneous results, but several studies indicated elevated risk in smokers, drinkers and betel quid users. Stronger effects consistently appeared in gene–environment interaction models. Polymorphisms in Phase I and Phase II metabolizing enzymes, especially GSTM1/GSTT1 null and selected CYP1A1/CYP2E1 variants, modulate susceptibility to OSCC in exposed individuals, supporting their potential use in risk stratification and targeted prevention strategies.