rs1341164 — CYP2C8

CYP2C8 rs1341164 — Taxane Metabolism and the Intronic Haplotype Tag

CYP2C8 is the liver's primary enzyme for metabolizing paclitaxel¹¹ paclitaxel
paclitaxel: a widely-used taxane chemotherapy drug for breast, ovarian, and lung cancers and its newer cousin [cabazitaxel | cabazitaxel: a second-generation taxane used in castration-resistant prostate cancer after docetaxel failure]. It is also responsible for clearing rosiglitazone and pioglitazone (thiazolidinedione diabetes drugs), repaglinide (a short-acting insulin secretagogue), and the anti-malarial amodiaquine. Beyond drug metabolism, CYP2C8 converts arachidonic acid into [epoxyeicosatrienoic acids (EETs) | EETs: potent vasodilatory and anti-inflammatory lipid mediators with cardioprotective and neuroprotective effects], making it a dual-purpose enzyme in both pharmacology and endogenous lipid signaling.

The rs1341164 variant lies within an intron of CYP2C8 — it does not change any amino acid — but intronic SNPs can still matter by tagging haplotype blocks that alter splicing efficiency, mRNA stability, or transcription factor binding sites. The evidence for rs1341164 is currently emerging: a single pharmacogenomic study has directly tested it, and the broader *IG haplotype literature provides indirect mechanistic context.

The Mechanism

rs1341164 is located at chromosome 10, position 95,041,116 (GRCh38), in intron 8/9 of CYP2C8 (HGVS: NC_000010.11:g.95041116T>C). As a C allele carrier, you may be tagging a haplotype group with reduced CYP2C8 expression or catalytic efficiency. The *IG haplotype study by Saito et al.²² *IG haplotype study by Saito et al.
Saito Y et al. CYP2C8 haplotype structures and their influence on pharmacokinetics of paclitaxel in a Japanese population. Pharmacogenet Genomics, 2007 found that CYP2C8 haplotypes harboring several intronic variations were associated with a 2.5-fold higher area under the curve (AUC) of the major paclitaxel metabolite 6α-hydroxypaclitaxel, consistent with reduced CYP2C8 clearance. Whether rs1341164 is a tag SNP for this haplotype group has not been formally confirmed.

The Evidence

The most direct evidence comes from a 2022 pharmacogenomics study of metastatic castration-resistant prostate cancer (mCRPC). Herrero Rivera et al.³³ Herrero Rivera et al.
Herrero Rivera D et al. Single-nucleotide polymorphism associations with efficacy and toxicity in metastatic castration-resistant prostate cancer treated with cabazitaxel. Pharmacogenomics, 2022 analyzed 56 SNPs across five drug-metabolism genes in 67 cabazitaxel-treated patients and found that rs1341164 C allele carriers had significantly better overall survival (hazard ratio 0.53 in multivariate analysis). The most plausible interpretation is that C allele carriers clear cabazitaxel more slowly, resulting in higher drug exposure and better tumor kill — consistent with the *IG haplotype's reduced clearance phenotype.

Parallel evidence exists for paclitaxel: Hertz et al.⁴⁴ Hertz et al.
Hertz DL et al. Genetic heterogeneity beyond CYP2C8*3 does not explain differential sensitivity to paclitaxel-induced neuropathy. Breast Cancer Res Treat, 2014 demonstrated in 412 breast cancer patients that CYP2C8 low-metabolizer status (combined *2, *3, *4 variants) increased peripheral neuropathy risk by 72% (HR 1.722, p=0.018). This raises the possibility that rs1341164 C-allele carriers — if they indeed clear paclitaxel more slowly — may face similar neurotoxicity risk, though this has not been directly studied.

Important caveat: The cabazitaxel study was small (n=67) and the authors explicitly described results as "hypothesis-generating." rs1341164 has no entry in ClinVar, no CPIC or DPWG guideline, and has not been replicated. The evidence level is emerging.

Practical Actions

The principal clinical implication is in taxane chemotherapy contexts (paclitaxel, docetaxel, cabazitaxel). If you carry the C allele and your oncologist is prescribing a taxane, this variant warrants discussion — not because it mandates dose changes, but because it may contribute to your overall CYP2C8 metabolizer phenotype. Formal pharmacogenomic testing using a certified panel (which covers the clinically established *2, *3, *4 alleles alongside less-characterized intronic variants) provides a more complete picture.

The EET-production aspect of CYP2C8 function is also relevant: since EETs are cardioprotective and vasodilatory, variants that alter CYP2C8 expression in vascular endothelium may modulate cardiovascular risk — though this pathway has not been directly studied for rs1341164.

Interactions

CYP2C8 activity interacts with CYP2C9 (encoded by the adjacent gene on chromosome 10q24.1) — inhibitors of one often affect the other. CYP2C8 is potently inhibited by gemfibrozil (a lipid-lowering drug), which can increase exposure to repaglinide by up to 8-fold; this interaction does not depend on rs1341164 genotype but is relevant context when CYP2C8 metabolizer phenotype is uncertain. For the EET pathway, rs1341164 may interact with soluble epoxide hydrolase (EPHX2) variants: CYP2C8 makes EETs and EPHX2 degrades them, so reduced CYP2C8 combined with reduced EPHX2 activity may alter EET balance in a cardiovascular-relevant direction.