Maximizing Detox Using Genomics
By Bonnie Nedrow, ND
The field of genomics is launching medicine into a new era where an individual’s genetic code is used to create unique treatments. Drug companies are developing designer drugs and patients are tracking personal health risks. Soon all health care professionals will either be versed in genetic applications or will be prompted to be knowledgeable by their patients.
One fascinating area in the interface of genetics and medicine is single nucleotide polymorphisms (SNPs). SNPs are solitary nucleotide substitutions that alter the function of specific genes. They provide powerful clues as to why people may experience varied reactions to the same nutritional and chemical exposures[i]. These clues can help refine our choice of therapeutics to epigenetically alter gene expression and restore balance in our patient’s health.
Depuration is one of the cornerstones of naturopathic medicine. In our modern world of ever-increasing exposure to man-made chemicals, the need for avoidance and removal of toxicants has never been greater. Knowledge of how SNPs impact biotransformation of chemical compounds allows us to create individualized detoxification (also referred to as depuration) treatment plans.
While all cells have the capacity to process toxic compounds and eliminate waste, hepatic biotransformation is the hub of chemical metabolism. In the liver, lipophilic compounds are first degraded in phase I via the cytochrome p450 system. Phase I produces intermediates that are more reactive and therefore more damaging than the original toxin. Phase II conjugates these toxic intermediates into hydrophilic compounds. Phase III is the removal of end products to the extracellular environment via efflux pumps and ultimately their excretion in urine and bile.
To avoid flooding the system with toxic intermediates, it is essential to balance phase I and II enzymes. One fascinating pattern of SNPs in biotransformation is that polymorphisms in phase I tend to speed up the enzyme while polymorphisms in phase II tend to slow down transformation. Combinations of key SNPs may increase an individual’s susceptibility to chemicals through overproduction of toxic intermediates.
There is an abundance of research on the health impacts of specific SNPs. In addition, many chemical and nutrient substances have been identified that induce, suppress or are substrates for hepatic enzymes. A foray into the research can begin with enzymes that meet the following criteria: They are known to be key players in depuration, there is a plentiful body of research, and they are compounds that are reported on available tests.
CYP1B1 is one of the key players that currently meets the above criteria. It is overexpressed in a wide range of human cancers, including breast, colon, lung, esophagus, skin, lymph node, brain and testis. This enzyme is involved in estrogen metabolism and primarily hydroxylates E2 at the C-4 position, producing a carcinogenic estrogen intermediate[ii]. CYP1B1 is also an important metabolizer of chemically diverse carcinogenic compounds. It is inducible by cigarettes, BPA and dioxin[iii]. Induction speeds up enzymatic activity and contributes to increased toxic intermediates, especially when a person is also exposed to the compounds metabolized by CYP1B1.
In estrogen metabolism, CYP1B1 catalyzes 17-beta-estradiol to the catechol estrogens 2-OHE2 and 4-OHE2. The phase II enzyme, catechol-O-Methyltransferase (COMT), methylates these carcinogenic intermediates and produces the less toxic compounds methoxylated estrogens[iv]. Individuals with the wild type COMT Val/Val genotype have a three- to four-fold higher activity of the COMT enzyme than those with Met/Met genotype. Heterozygous Val/Met exhibit intermediate enzyme activity.
Many phytonutrients can be used to modify the imbalance of a genetic pattern that accelerates phase I estrogen metabolism via CYP1B1 SNPs, combined with COMT Met/Met genotype that slows phase II metabolism. By manipulating epigenetic triggers, we can shift estrogen metabolism in an individual to reduce risk of overproduction of carcinogenic intermediates.
However, it is crucial to remember that SNPs are clues not formulas. As has been stated by many astute clinicians versed in the analysis of SNPs and disease, “treat the person not the SNP”. Tests providing the genomic pattern must be coupled with tests showing phenotypic outcomes. An extensive environmental history, with a timeline that illustrates nutrition habits and chemical exposures over the patient’s lifespan, will also be useful.
There are many excellent tests to consider. An affordable option for SNP testing is 23andMe. There are several free sites, such as Genetic Genie and StrateGene to analyze the results. Next choose functional tests to assess current areas of concern based on the patient’s chief complaint and presenting symptoms. You may also want to order toxicant panels, such as urine toxic metal test or an extensive serum test looking at a variety of toxicants. Panel choice can be determined based on the history of exposure, both current and past, and your patient’s presentation.
My favorite functional test is a hepatic panel including AST, ALT, GGT and bilirubin. While there are more sensitive and specific liver function tests available, its affordability allows for repeat testing to assess treatment. GGT in particular has been suggested to be a biomarker for xenobiotic exposures and body burden. Moderate elevation of GGT, within its normal range, has been linked to various chemicals including lead, cadmium, organochlorine pesticides, dioxin[v] and PCBs[vi].
Many foods, herbs and supplements traditionally found in naturopathic depuration protocols can epigenetically alter SNPs. For example, cruciferous vegetables are an excellent substrate for glutathione metabolism and also induce CYP1A2. For individuals with a CYP1A2 SNP, cruciferous vegetables could lead to a net increase in carcinogenesis. However, adding apiaceous vegetables and herbs (carrots, celery, parsnips, dill, fennel, cumin, caraway & coriander) which block CYP1A2, allows for a net reduction in CYP1A2 with an induction of glutathione metabolism[vii].
Antioxidants of all types have an impact on glutathione metabolism. For individuals with null GSTT1 and/or GSTM1, higher doses of vitamin C can help compensate. Even a modest amount of supplemental vitamin C, such as found in a multivitamin, was shown to compensate for these SNPs[viii]. In an elegant study of smokers, 8-week grape juice supplementation significantly decreased DNA damage, even in individuals with GSTM1 and GSTM2 null genotypes[ix].
Many other phytochemicals from foods and herbs have the capacity to slow down phase I while speeding up phase II. These compounds have long been recognized as healing substances with powerful phytochemicals. It is exciting to explore their genetic impact at the enzyme level. Some familiar players in this category are resveratrol, genistein, quercetin, naringenin, and extracts from green tea, black tea, apples, blueberries and chokeberries[x].
In 2017, we are in the infancy stage of understanding how xenobiotics and phytonutrients interact with the human genome[xi]. New research is being conducted daily, expanding this database and sometimes refuting what we thought we knew. At other times, this line of research gives greater weight to historic depuration practices. In the end, there is no going back; the future is here to stay.
[i] Tesfaye M Baye, Tilahun Abebe, and Russell A Wilke. Genotype–environment interactions and their translational implications. Per Med. 2011 January ; 8(1): 59–70.
[ii] Lavigne JA1, Goodman JE, Fonong T et al. The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. Cancer Res. 2001 Oct 15;61(20):7488-94.
[iii] Zienolddiny S1, Campa D, Lind HA et al. A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers. Carcinogenesis. 2008 Jun;29(6):1164-9.
[vi] Serdar B1, LeBlanc WG, Norris JM, Dickinson LM,Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides (OCPs) on immune cells and blood biochemistry measures: a cross-sectional assessment of the NHANES 2003-2004 data. Environ Health. 2014 Dec 16;13:114.
[vii] Peterson S1, Schwarz Y, Li SS, et al. CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial.Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):3118-25.
[ix] Mi-Ran Cho, Jeong-Hwa Han, Hye-Jin Lee, Purple grape juice supplementation in smokers and antioxidant status according to different types of GST polymorphisms. J Clin Biochem Nutr. 2015 Jan; 56(1): 49–56.
[x] Jia-Ching Wu, Ching-Shu Lai, Mei-Ling Tsai, Chi-Tang Ho, Ying-Jan Wang, Min-Hsiung Pan. Chemopreventive effect of natural dietary compounds on xenobiotic-induced toxicity. Journal of Food and Drug Analysis. January 2017Volume 25, Issue 1, Pages 176–186.
[xi] Hodges RE, Minich DM, Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J Nutr Metab. 2015;2015:760689