rs1045642 — ABCB1 C3435T

The Efflux Pump That Doesn't Change — But Everything Changes Anyway

P-glycoprotein is your body's master bouncer, stationed at critical barriers — the gut, liver, kidneys, blood-brain barrier — pumping hundreds of drugs and toxins back out before they can accumulate. The ABCB1 gene¹¹ ABCB1 gene
Also known as MDR1 (multidrug resistance 1), this gene encodes a 1280-amino-acid transmembrane pump on chromosome 7 creates this ATP-dependent efflux transporter, determining how much of a drug actually reaches its target versus getting ejected back into circulation. C3435T is a synonymous variant — same amino acid (isoleucine at position 1145), different nucleotide — yet it profoundly alters P-gp expression and function.

The Mechanism: When Silence Isn't Silent

Despite encoding the same amino acid, the T variant creates a rare codon²² rare codon
Less frequently used in human protein synthesis, slowing translation rate that changes how the mRNA folds during translation. Wang et al. demonstrated³³ Wang et al. demonstrated
Using allele-specific expression analysis in human liver samples that the 3435T allele produces less stable mRNA (C/T ratios 1.06-1.61), reducing P-gp expression by altering mRNA secondary structure. The result: TT homozygotes have 30-50% lower intestinal P-gp expression than CC carriers, leading to higher plasma drug levels for P-gp substrates after oral administration.

Kimchi-Sarfaty's group showed⁴⁴ Kimchi-Sarfaty's group showed
Published in Science 2007 that the synonymous change also alters co-translational protein folding, creating a P-gp structure with different substrate specificity despite similar protein levels. The rare codon slows translation, giving the nascent protein extra time to fold differently, changing which drugs fit the efflux pump.

The Evidence: Hundreds of Drugs, Inconsistent Results

The Hoffmeyer study⁵⁵ Hoffmeyer study
2000 landmark paper with 21 healthy volunteers first reported that TT homozygotes had significantly lower duodenal P-gp expression and 1.5-fold higher plasma digoxin concentrations compared to CC homozygotes. Since then, hundreds of studies have examined C3435T effects on drug disposition, with maddeningly inconsistent results.

For immunosuppressants: Haufroid et al. (n=100 renal transplant patients)⁶⁶ Haufroid et al. (n=100 renal transplant patients) found TT carriers needed lower tacrolimus doses to achieve target levels, though effects were modest compared to CYP3A5 polymorphisms. Meta-analyses show small but significant associations with cyclosporine pharmacokinetics, though clinical utility remains debated.

For antidepressants: Saiz-Rodríguez et al. (n=473 healthy volunteers)⁷⁷ Saiz-Rodríguez et al. (n=473 healthy volunteers) found TT individuals showed lower olanzapine clearance but enhanced elimination of risperidone and trazodone, suggesting drug-specific effects. The authors concluded that C3435T affects some CNS drugs but that ABCB1 haplotypes (combinations with rs1128503 and rs2032582) may be more predictive than single SNPs.

The inconsistency stems from several factors: C3435T is in strong linkage disequilibrium⁸⁸ linkage disequilibrium
Two SNPs inherited together more often than by chance with rs1128503 (C1236T) and rs2032582 (G2677T/A), forming common haplotypes. Drug response depends on substrate-specific affinity for different P-gp conformations. CYP3A4/5 metabolism often matters more than P-gp transport. Tissue-specific effects vary (intestine vs. blood-brain barrier). PharmGKB assigns Level 3 evidence (single or non-replicated studies) for most C3435T-drug pairs.

Practical Implications: Know Your Substrates

P-glycoprotein handles hundreds of structurally diverse substrates⁹⁹ hundreds of structurally diverse substrates: cardiac drugs (digoxin, verapamil, diltiazem), immunosuppressants (cyclosporine, tacrolimus), cancer chemotherapy (doxorubicin, vincristine, paclitaxel, imatinib), antiretrovirals (ritonavir, saquinavir), opioids (morphine, fentanyl, methadone), antihistamines (fexofenadine), and many others.

The TT genotype generally means higher drug bioavailability (more gets in) but also higher CNS penetration and potentially more side effects. However, the clinical significance varies dramatically by drug, dose, and individual. For narrow therapeutic index drugs like digoxin or immunosuppressants, even modest effects matter. For most other medications, dose adjustments based on clinical response (therapeutic drug monitoring) outweigh genetic prediction.

Interactions: The Haplotype Matters More

C3435T rarely acts alone. It forms two major haplotypes with rs1128503 (C1236T) and rs2032582 (G2677T/A): the reference haplotype (C-G-C, designated ABCB1*1) and the variant haplotype (T-T-T, designated ABCB1*13). Studies increasingly show that haplotype analysis predicts drug response better than single SNPs, since the combined effect of multiple linked variants determines overall P-gp expression and function. Population frequencies vary dramatically¹⁰¹⁰ Population frequencies vary dramatically: the 3435C allele ranges from 34% in some Asian populations to 90% in West African populations.