rs3745274 — CYP2B6 516G>T

CYP2B6 516G>T — A Pharmacogenetic Variant with Wide-Ranging Drug Metabolism Effects

CYP2B6 is a liver enzyme responsible for metabolizing approximately 8% of prescription drugs, including several critical medications for HIV, pain, depression, and cancer. Despite comprising only 1-4% of total hepatic cytochrome P450 content, CYP2B6 is the primary metabolizer¹¹ CYP2B6 is the primary metabolizer
CYP2B6 is the major catalyst of metabolism for efavirenz, cyclophosphamide, bupropion, methadone, ketamine, and propofol for numerous clinically important drugs. The 516G>T variant (also known as CYP2B6*9 or Q172H) is one of the most common and clinically significant genetic variations in this gene, dramatically reducing enzyme activity and leading to elevated drug levels and increased toxicity risk.

The Mechanism

The 516G>T polymorphism changes codon 172 from glutamine (Q) to histidine (H) in the CYP2B6 protein. The variant triggers aberrant splicing²² The variant triggers aberrant splicing
Single nucleotide polymorphism c.516G>T is responsible for decreased expression and activity of CYP2B6 in liver through aberrant splicing during mRNA processing, resulting in transcripts that lack exons 4-6 and produce non-functional protein. This splicing defect reduces both CYP2B6 mRNA and protein expression in the liver, with homozygous TT carriers showing approximately 70% reduced enzyme activity compared to GG wild-type individuals. The mechanism is dose-dependent: heterozygotes (GT) show intermediate reduction, demonstrating codominant inheritance. This variant is found alone in CYP2B6*9 but also exists in combination with another SNP (785A>G) in the more common CYP2B6*6 allele.

The Evidence

Haas et al. (2004)³³ Haas et al. (2004)
Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study studied 157 HIV-infected patients and found homozygosity for 516G>T was present in 20% of African Americans versus 3% of European Americans. The median 24-hour area under the curve of efavirenz was approximately 3-fold higher in TT homozygotes versus GG homozygotes, with intermediate levels in GT heterozygotes. CNS side effects at week 1 were significantly associated with the T allele (p = 0.036). This work established the clinical relevance of the variant and led to CPIC Level A guidelines⁴⁴ CPIC Level A guidelines
Clinical Pharmacogenetics Implementation Consortium guideline for CYP2B6 and efavirenz-containing antiretroviral therapy recommending dose reductions for TT carriers.

For methadone, Kharasch et al. (2015)⁵⁵ Kharasch et al. (2015)
Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance, and metabolism demonstrated that 516G>T genotype was the primary determinant of methadone disposition. In vitro studies showed CYP2B6.6 enzyme activity⁶⁶ CYP2B6.6 enzyme activity
Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6 toward methadone was reduced to one-third to one-fourth that of wild-type enzyme at clinically relevant concentrations. Multiple studies have linked 516G>T with enhanced risk of methadone fatalities⁷⁷ enhanced risk of methadone fatalities
Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities due to accumulation of (S)-methadone, which prolongs the QT interval and increases cardiac risk.

Population frequencies of the T allele vary dramatically by ancestry: approximately 43% in African populations, 28-30% in European and South Asian populations, 29% in Latino populations, and 18% in East Asian populations. This makes the variant one of the most ancestry-differentiated pharmacogenes.

Practical Implications

The 516G>T variant affects multiple drug classes. For HIV treatment with efavirenz, TT carriers experience substantially higher plasma concentrations, increasing risk of neuropsychiatric side effects including dizziness, insomnia, abnormal dreams, confusion, and suicidal ideation. CPIC guidelines recommend considering an alternative antiretroviral or reduced dose (400 mg or 200 mg instead of standard 600 mg daily) for intermediate and poor metabolizers.

For pain management with methadone, slower metabolism leads to drug accumulation, prolonged QT intervals, and increased risk of respiratory depression and cardiac arrhythmias. Dose adjustments and therapeutic drug monitoring are especially important. For depression treatment with bupropion, reduced conversion to the active metabolite hydroxybupropion may diminish antidepressant and smoking cessation efficacy.

For cancer chemotherapy with cyclophosphamide, the clinical implications are complex and substrate-dependent. While 516G>T reduces enzyme expression, some studies suggest the variant may actually increase cyclophosphamide bioactivation through alternative mechanisms, highlighting the substrate-specific nature of CYP2B6 pharmacogenetics.

Interactions

The 516G>T variant (CYP2B6*9) is frequently found in combination with the 785A>G variant, forming CYP2B6*6, the most common reduced-function haplotype globally. The compound effect of these variants produces more severe enzyme deficiency than either alone. Additionally, CYP2B6 activity is highly inducible by rifampin, efavirenz itself, and other drugs, which can partially overcome genetic deficiency but complicates dosing in patients on combination therapy. CYP2B6 polymorphisms may interact with variants in other metabolizing enzymes (CYP3A4, CYP2C19, CYP2D6) that serve as alternative pathways for some substrates, creating complex pharmacokinetic profiles that require careful clinical monitoring.