rs1048943 — CYP1A1 Ile462Val (*2C)

CYP1A1 Ile462Val — The Smoke and Estrogen Activator

Cytochrome P450 1A1 (CYP1A1) is a Phase I detoxification enzyme¹¹ Phase I detoxification enzyme
Phase I enzymes oxidize, reduce, or hydrolyze foreign compounds to make them more reactive — a necessary step before Phase II enzymes can conjugate them for excretion with a dual role that makes it both protector and potential threat. On one hand, CYP1A1 initiates the breakdown of polycyclic aromatic hydrocarbons (PAHs)²² polycyclic aromatic hydrocarbons (PAHs)
Flat, multi-ringed carbon compounds formed during incomplete combustion of organic matter — found in cigarette smoke, grilled meat, vehicle exhaust, and industrial pollution, dioxins, and other environmental pollutants. On the other hand, the intermediates it creates — reactive epoxides and diol-epoxides — can damage DNA if not swiftly neutralized by Phase II enzymes like glutathione S-transferase (GST). CYP1A1 also metabolizes estrogens into catechol estrogens, adding a hormonal dimension to its significance.

The rs1048943 variant (also called *2C or m2) substitutes isoleucine with valine at position 462, near the heme-binding domain³³ heme-binding domain
The catalytic core of all cytochrome P450 enzymes, where iron-bound heme activates molecular oxygen to insert into substrate molecules of the enzyme. This amino acid change increases CYP1A1's catalytic activity, meaning the variant enzyme produces reactive intermediates at a faster rate.

The Mechanism

CYP1A1 expression is primarily regulated by the aryl hydrocarbon receptor (AHR)⁴⁴ aryl hydrocarbon receptor (AHR)
A ligand-activated transcription factor that senses environmental chemicals and activates detoxification gene expression; see rs2066853 in this encyclopedia. When PAHs, dioxins, or certain dietary compounds (like indole-3-carbinol from cruciferous vegetables) bind AHR, it translocates to the nucleus and switches on CYP1A1 transcription through xenobiotic response elements (XREs)⁵⁵ xenobiotic response elements (XREs)
DNA sequences with the core motif 5'-TNGCGTG-3' in the promoters of AHR target genes. The Ile462Val substitution does not affect CYP1A1 expression levels — it affects what happens after the protein is made. The valine at position 462 alters the geometry of the active site near the heme group, resulting in approximately two-fold higher catalytic activity⁶⁶ two-fold higher catalytic activity
Cosma G et al. Relationship between genotype and function of the human CYP1A1 gene. J Toxicol Environ Health, 1993 and increased mutagenic activation of PAH substrates.

CYP1A1 also catalyzes the 2-hydroxylation and 4-hydroxylation of estradiol⁷⁷ 2-hydroxylation and 4-hydroxylation of estradiol
Converting estradiol into catechol estrogens; the 2-hydroxy pathway is the dominant route and is generally considered protective, while 4-hydroxylation produces more genotoxic quinone intermediates. The Val462 variant's increased catalytic activity extends to estrogen substrates, potentially shifting the balance of estrogen metabolite production.

The Evidence

Overall cancer risk. A comprehensive meta-analysis of 198 publications⁸⁸ meta-analysis of 198 publications
Wu B et al. MspI and Ile462Val polymorphisms in CYP1A1 and overall cancer risk: a meta-analysis. PLoS One, 2013 found significantly elevated cancer risk associated with the Ile462Val polymorphism across all genetic models studied. The effect was observed in both Asian and Caucasian populations.

Lung cancer. A meta-analysis of 43 case-control studies⁹⁹ meta-analysis of 43 case-control studies
Ji YN et al. CYP1A1 Ile462Val polymorphism contributes to lung cancer susceptibility among lung squamous carcinoma and smokers: a meta-analysis. PLoS One, 2012 comprising 19,228 subjects found that Val/Val carriers had an odds ratio of 1.22 (95% CI 1.08-1.40) compared with Ile/Ile. The dominant model (any Val allele) showed OR 1.15 (95% CI 1.07-1.23). The association was significant in smokers but not in non-smokers, highlighting the gene-environment interaction: the increased enzyme activity only becomes a problem when there is PAH substrate to activate.

Colorectal cancer. A meta-analysis of 13 case-control studies¹⁰¹⁰ meta-analysis of 13 case-control studies
He XF et al. CYP1A1 Ile462Val polymorphism contributes to colorectal cancer risk: a meta-analysis. World J Gastroenterol, 2011 with 5,336 cases and 6,226 controls found Val/Val carriers at increased risk (OR 1.47, 95% CI 1.16-1.86). The recessive model (Val/Val vs Ile/Ile + Ile/Val) reached OR 1.49 (95% CI 1.18-1.88), suggesting the risk concentrates in homozygous carriers.

Gene-environment synergy. A pooled analysis of Caucasian non-smokers¹¹¹¹ pooled analysis of Caucasian non-smokers
Vineis P et al. CYP1A1 and GSTM1 genetic polymorphisms and lung cancer risk in Caucasian non-smokers: a pooled analysis. Carcinogenesis, 2003 found that combining the CYP1A1 Val allele with the GSTM1 null genotype (absent glutathione conjugation) produced a dramatic OR of 4.67 (95% CI 2.00-10.9). This illustrates the Phase I/Phase II balance principle: faster activation (CYP1A1 Val) without adequate conjugation (GSTM1 null) allows reactive intermediates to accumulate and damage DNA.

Breast cancer. Despite the estrogen metabolism connection, a HuGE review of 17 studies¹²¹² HuGE review of 17 studies
Masson LF et al. Cytochrome P-450 1A1 gene polymorphisms and risk of breast cancer: a HuGE review. Am J Epidemiol, 2005 with over 5,000 combined subjects found no consistent overall association. However, long-term smokers carrying the variant showed elevated breast cancer risk, again pointing to gene-environment interaction rather than genotype acting alone.

Population Distribution

The Val462 allele shows striking population stratification. It reaches its highest frequency in Latino/Admixed American populations (~36%), followed by East Asians (~23%) and South Asians (~12%). In contrast, it is rare in Europeans (~3%) and very rare in Africans (~1%). This distribution likely reflects different evolutionary pressures related to diet and environmental exposures across populations. The Greenlandic Inuit, who consume large amounts of marine mammal fat containing persistent organic pollutants, have among the highest reported frequencies (~46%).

Practical Implications

The key insight from this research is that the CYP1A1 Val462 variant is not a cancer risk gene in isolation — it becomes a risk factor when combined with environmental exposure to PAHs. Carriers who avoid or minimize PAH exposure can substantially reduce the impact of the variant. Practical steps include modifying cooking methods to reduce PAH formation, avoiding tobacco smoke exposure, and consuming cruciferous vegetables that support Phase II conjugation of the reactive intermediates CYP1A1 generates.

Interactions

AHR (rs2066853): Since AHR controls CYP1A1 transcription, the combination of AHR genotype and CYP1A1 genotype determines the full picture of PAH metabolism. Altered AHR signaling (rs2066853 A allele) could modify how much CYP1A1 is induced in response to pollutant exposure, potentially amplifying or dampening the impact of the Ile462Val variant on reactive intermediate production.

CYP1A1*2A (rs4646903): The MspI polymorphism in the 3' flanking region of CYP1A1 increases gene expression through altered mRNA stability. When found on the same haplotype as Ile462Val (the *2B haplotype), the combined effect is both more enzyme and more active enzyme — a double hit that increases PAH activation capacity. This haplotype combination is particularly common in East Asian and Latino populations.