rs1056836 — CYP1B1 Leu432Val

CYP1B1 Leu432Val — The Estrogen and Toxin Activator

CYP1B1 is a Phase I cytochrome P450 enzyme¹¹ Phase I cytochrome P450 enzyme
Phase I enzymes add reactive groups (usually hydroxyl -OH) to molecules, making them more water-soluble and preparing them for Phase II conjugation and excretion with a dual role that makes it uniquely important in cancer biology. First, it converts estradiol into 4-hydroxyestradiol (4-OH-E2)²² 4-hydroxyestradiol (4-OH-E2)
A catechol estrogen metabolite that can be further oxidized to reactive quinones capable of forming depurinating DNA adducts — direct chemical damage to DNA, the most genotoxic of the estrogen metabolites. Second, it activates environmental procarcinogens including polycyclic aromatic hydrocarbons (PAHs) from tobacco smoke and charred foods, and heterocyclic amines from cooked meat. The Leu432Val variant (rs1056836) sits in the heme-binding domain³³ heme-binding domain
The catalytic core of the enzyme where the iron-containing heme group binds substrates and performs oxidation reactions and alters the enzyme's catalytic properties toward both substrates.

Unlike most liver-dominant CYP450 enzymes, CYP1B1 is primarily expressed in extrahepatic tissues — breast, uterus, ovary, prostate, lung, and kidney — precisely the organs where its estrogen-metabolizing and carcinogen-activating roles matter most. Its expression is controlled by the aryl hydrocarbon receptor (AHR)⁴⁴ aryl hydrocarbon receptor (AHR)
A ligand-activated transcription factor that responds to environmental pollutants, dietary compounds from cruciferous vegetables, and tryptophan metabolites, meaning that exposure to dioxins, PAHs, or cruciferous vegetable compounds like DIM and I3C directly upregulates CYP1B1 activity.

The Mechanism

The rs1056836 variant causes a leucine-to-valine substitution at position 432 in the heme-binding domain. On the genomic plus strand (as reported by 23andMe), the G allele encodes leucine (wild-type) and the C allele encodes valine (variant). The amino acid change alters the active site geometry, shifting the enzyme's preference between competing hydroxylation pathways.

Enzyme kinetics studies⁵⁵ Enzyme kinetics studies
Shimada T et al. Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis, 1999 showed that Val432 forms of CYP1B1 produce a higher ratio of 4-hydroxyestradiol to 2-hydroxyestradiol compared to Leu432 forms. The 4-hydroxylation pathway is concerning because 4-OH-E2 can be oxidized to semiquinones and quinones⁶⁶ semiquinones and quinones
Reactive electrophiles that form covalent bonds with DNA bases, creating unstable depurinating adducts that leave behind mutagenic apurinic sites that directly damage DNA. The 2-hydroxylation pathway, by contrast, produces less genotoxic metabolites.

A separate study by Li et al.⁷⁷ study by Li et al.
Li DN et al. Polymorphisms in P450 CYP1B1 affect the conversion of estradiol to the potentially carcinogenic metabolite 4-hydroxyestradiol. Pharmacogenetics, 2000 found that the Val432-to-Leu change increases the Km (reduces binding affinity) for estradiol hydroxylation at least 3-fold, meaning the Leu432 form is less efficient at metabolizing estradiol overall. The net effect of the Val432 variant is both greater throughput and a more dangerous product ratio.

The safety of CYP1B1's reactive metabolites depends entirely on downstream Phase II enzymes — GSTP1, GSTM1, and NQO1 — which conjugate and neutralize the catechol estrogen quinones before they can damage DNA. When Phase II capacity is insufficient to handle the Phase I output, oxidative damage accumulates.

The Evidence

Endometrial cancer. A meta-analysis of 12 studies⁸⁸ meta-analysis of 12 studies
Wang F et al. Association of CYP1B1 gene polymorphisms with susceptibility to endometrial cancer: a meta-analysis. Eur J Cancer Prev, 2011 encompassing 3,605 cases and 5,692 controls found that the Val432 allele significantly increases endometrial cancer risk (OR 1.23, 95% CI 1.06-1.43). This is biologically coherent: the endometrium is an estrogen-responsive tissue where CYP1B1 is expressed, and increased 4-OH-E2 production would create local genotoxic exposure.

Lung cancer. A meta-analysis of 10 studies⁹⁹ meta-analysis of 10 studies
Xu W et al. Current evidence on the relationship between CYP1B1 polymorphisms and lung cancer risk: a meta-analysis. Mol Biol Rep, 2012 with 7,067 cases and 9,374 controls found that individuals homozygous for Val432 had a 39.7% higher lung cancer risk compared to Leu432 homozygotes. This likely reflects CYP1B1's role in activating PAHs from tobacco smoke rather than estrogen metabolism.

Breast cancer. Despite the strong mechanistic rationale, epidemiological evidence for breast cancer has been inconsistent. A comprehensive meta-analysis¹⁰¹⁰ comprehensive meta-analysis
Liu JY et al. Association between the CYP1B1 polymorphisms and risk of cancer: a meta-analysis. Mol Genet Genomics, 2015 found the Leu432Val variant associated with endometrial and lung cancer risk but not consistently with breast cancer across populations. Gene-environment interactions — particularly smoking status and Phase II enzyme capacity — may explain the inconsistent breast cancer findings.

Bone density. A study in postmenopausal women¹¹¹¹ study in postmenopausal women
Napoli N et al. The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density. Bone, 2009 found that Leu432 allele carriers (on the coding strand) had significantly higher urinary estrogen metabolites and lower bone mineral density at the lumbar spine (0.931 vs 1.009 g/cm2, p=0.03) and femoral neck (0.693 vs 0.748 g/cm2, p=0.03) compared to Val/Val homozygotes. This paradoxical finding — where higher estrogen catabolism leads to a hypoestrogenic state — suggests the overall rate of estrogen metabolism matters for bone health alongside the specific pathway balance.

Practical Implications

The actionable message for Val432 carriers centers on supporting Phase II detoxification to safely neutralize the increased 4-hydroxyestradiol output. Cruciferous vegetables (broccoli, Brussels sprouts, cauliflower, kale) contain indole-3-carbinol (I3C) and sulforaphane¹²¹² indole-3-carbinol (I3C) and sulforaphane
I3C is converted to DIM in the stomach; sulforaphane activates Nrf2, the master regulator of Phase II enzyme expression that both modulate CYP1B1 activity and upregulate Phase II enzymes including glutathione S-transferases and NQO1. Diindolylmethane (DIM)¹³¹³ Diindolylmethane (DIM)
The acid-catalyzed dimer of I3C formed in the gut; available as a supplement shifts estrogen metabolism toward the protective 2-hydroxylation pathway and away from the genotoxic 4-hydroxylation pathway.

Minimizing exposure to PAH-rich environments (tobacco smoke, heavily charred foods, industrial pollutants) is particularly important for Val432 carriers, since CYP1B1 both responds to AHR activation by these compounds and more efficiently converts them to DNA-damaging metabolites.

For women, monitoring estrogen-related health markers becomes more relevant with this variant, especially in the context of hormone replacement therapy or conditions associated with estrogen exposure.

Interactions

The most critical interaction is with Phase II conjugation enzymes. GSTP1 (rs1695), GSTM1 (null/present), and NQO1 (rs1800566) detoxify the reactive catechol estrogen quinones produced by CYP1B1. A Val432 carrier with compromised Phase II capacity (e.g., GSTM1 null deletion or NQO1*2 homozygosity) faces a compounded risk: increased production of reactive metabolites with decreased capacity to neutralize them. Published studies have confirmed that combined CYP1B1/GSTM1/GSTP1 genotypes modify cancer risk more than any single variant alone.

The AHR variant rs2066853 is also relevant because AHR controls CYP1B1 transcription. Altered AHR signaling could modify the degree to which environmental exposures induce CYP1B1 expression, affecting the overall burden of Phase I metabolite production.

COMT (catechol-O-methyltransferase) provides another detoxification route for catechol estrogens via methylation. Carriers of both CYP1B1 Val432 and slow COMT variants may have a more unfavorable estrogen metabolite profile, as both increased 4-OH-E2 production and decreased methylation clearance compound the genotoxic burden.