Liver Detox Genes – CYP1A1

Liver DetoxGenesThis is part of an ongoing series on the genes involved in phase I and phase II detoxification.

CYP1A1 is a gene that codes for the enzyme of the same name that is part of the phase I metabolism of some drugs and xenobiotics in the liver.  It is also involved in the activation of aromatic hydrocarbons (PAH) in the intestines, thus playing a role in smoking-related cancers from the activation of the aromatic hydrocarbons. Aromatic hydrocarbons are also found in wood smoke, vehicle exhausts, asphalt, and charred meats.

In addition to exogenous toxins, CYP1A1 is also involved in the metabolism of 17β-estradiol as well as the polyunsaturated fats arachidonic acid and DHA.

The CYP450 family of genes have various polymorphisms that can either slow down or speed up the rate of the enzyme. Most of the polymorphisms are identified with a * and a number.  Below is a list of common polymorphisms for CYP1A1.


CYP1A1*2:
There are several studies showing a relationship between the CYP1A1*2 (rs1048943, C allele) and estrogen-related cancers, but the results vary according to population and possibly diet:

  • A Chinese study showed that the CYP1A1*2 polymorphism had a lower risk of breast cancer.
  •  Another study showed that those with CYP1A1*2 has more of an inhibition with natural polyphenols than those without the polymorphism.
  • study showed that CYP1A1*2 has a significantly higher activity level of estrogen metabolism.   “Taken together, from a biochemical point of view, the extraordinary high estrogen-2-hydroxylase activity of the CYP1A1.2 (Ile562Val) variant may either increase or reduce the susceptibility to cancer depending on its combination with other genetic and environmental risk factors…”

Diet plays a role here as well.  A study found that those with the CYP1A1*2 genotype (rs1058943 CC) had a greater reduction in colon cancer risk with a diet high in polyphenols (found in veggies and fruit) than those with rs1058943 TT.

Other genes, such as COMT, also come into play when looking at estrogen-related cancer risk. One speculation is that: “Considering the metabolic fate of the 2-hydroxyestrogens produced by CYP1A1, a particular risk may arise if CYP1A1*2 (Ile462Val) occurs simultaneously with both (a) a “low-activity” COMT allele (COMT-L, 108/158Met substitution), and/or (b) a defect in one of the glutathione-S-transferase (GST) genes required to detoxify the quinones by conjugation with glutathione (e.g., in carriers of the GSTM1 and/or GSTT1 null genotypes). In theory, this combination would cause an accumulation of 2-hydroxylated” [study]

Check your 23andMe results for rs1048943 (v.4 only):

  • TT: Normal
  • CT:  carrier of one CYP1A1*2 allele; smokers have higher risk of lung cancers; higher activity in estrogen metabolism
  • CC: CYP1A1*2; higher risk of oral cancer & lung cancers in smokers; higher activity in estrogen metabolism [study],[study], [study]

 

CYP1A1*4:
The CYP1A1*4 variant has a somewhat increased enzyme activity.  Some studies show it to be protective against certain cancers, and other show it to slightly increase risk depending on the population.[study] [study]  One reason for the conflicting studies may be because it is fairly rare to have a homozygous (TT) mutation, and the percentage of heterozygotes (GT) in Caucasian populations is less than 10%.

Some studies show that the CYP1A1*4 allele is protective against lung cancer.[study] A meta analysis found it to be a risk factor for thyroid cancer.[study]

Check your 23andMe results for rs1799814 (v.4 and v.5):

  • GG: Normal
  • GT: one CYP1A1*4 allele
  • TT: increased enzyme activity, CYP1A1*4 [study]

Diet and Lifestyle:

Those who have a CYP1A1*2 allele are likely at a higher risk for lung cancer and really, really should not smoke. So if you need yet another reason to stop smoking, this would be a big one.

CYP1A1 is inhibited by several natural polyphenols including St. John’s Wort, I3C, and resveratrol.[study] Foods containing I3C include broccoli and other cruciferous vegetables.  Resveratrol is found in grapes and red wine as well as in supplement form.

 

Leave a Reply

Your email address will not be published. Required fields are marked *