“Eighty-five percent of all methylation reactions occur in the liver, and the liver is also using the most oxygen in the body at rest. The liver uses about 27 percent of the body’s oxygen at rest—that’s more than the brain—so our liver is a very, very important organ” – Ben Lynch, Phd

When I wrote an article on methylation, I highlighted the notion that most of us are blissfully unaware of how complex our internal machinery is and how it works to keep us alive every waking moment. I’d like to continue my never-ending quest to inform the public about the brilliance of the human body and all its machinations. If you ask the average person what they associate the word “waste” with, in regard to the human body, they will likely say number 1 and 2 in the bathroom. I concur, yes, number 1 and 2 in the bathroom are valid examples of human “waste”, but the formation of urine and faeces are the result of a long chain of biochemical reactions. The real magic behind our intrinsic waste disposal system, lies at the core of all those biochemical reactions. 

The detoxification pathways are the cornerstone of the human waste disposal system. In essence, metabolic detoxification involves two processes that orchestrate the biotransformation and elimination of exogenous and endogenous toxicants. Exogenous toxicants are compounds that we consume or encounter, directly or indirectly, such as drugs or pollutants and chemicals that we inhale or absorb through the skin, whereas endogenous toxicants are by-products of our metabolic processes, such as bacterial endotoxins. 

Detoxification occurs via two phases (or processes), referred to as phase 1 and phase 2 (also known as conjugation) and both rely on enzymes to facilitate the transformation of toxicants (Cline, 2015). Phase 1 involves the addition of oxygen to form a reactive site on the toxic compound and phase 2 is the process of adding a water-soluble group to the reactive site, making the compound water-soluble and excretable (Hodges & Minich, 2015). The enzymes that catalyse most of phase 1 reactions are called cytochrome P450 enzymes, which are mostly located in the liver, and their primary mode of action is to oxygenate toxicants. Additionally, they are involved in drug/steroid and fatty acid metabolism, steroid and bile acid synthesis, and vitamin D activation (Danielson, 2002). Below is a table outlining the processes behind phase 1 and 2 biotransformation, the prerequisite enzymes, and supportive nutrients for each step.   

Phase 1 (CYP450 enzymes)	Phase 2 (conjugation)
Oxidation	Sulfation Sulfotransferases Requires inorganic sulphate (dietary sources of sulphur, such as allium vegetables) Metabolism of thyroid hormone, estrogen and other androgens Supported by caffeine, retinoic acid (vitamin A),
Reduction	Glucuronidation Glucuronyl transferases Enhances elimination of toxins in urine and faeces Metabolizes steroid hormones and bilirubin  Supported by cruciferous vegetables, resveratrol, citrus fruits, Ellagic acid (polyphenol in berries), Ferulic acid (common polyphenol)
Hydrolysis	Glutathione conjugation Glutathione transferases Methionine and cysteine are necessary precursors   Attach a glutathione group to a biotransformed metabolite Supported by cruciferous and allium vegetables, citrus fruits, resveratrol, quercetin
Hydration	Acetylation N-acetyl-transferases Transfers acetyl group to convert aromatic amines/hydrazines to aromatic amides/hydrazides (drug metabolism) Supported by quercetin
Dehalogenation	Amino acid conjugation  Amino acid transferases Amino acids are used for binding to metabolites for excretion Dietary protein is essential (glycine, taurine, glutamine, ornithine (arginine and magnesium), arginine
Inducers/supporters of CYP enzymes Cruciferous vegetables Resveratrol Green/black tea Curcumin (turmeric polyphenol) Ellagic acid (polyphenol in berries) Quercetin (common polyphenol)	Methylation (N-/O-methyltransferases) The conjugation donor compound in methyltransferase reactions is methionine from SAMe (S-adenosyl-L-methionine) Methionine, vitamin B12/B6, betaine, folate, and magnesium are prerequisites for methylation (Hodges & Minich, 2015)

Keep in mind that phase 1 does not rely solely on the CYP group of enzymes, as alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), ester and amide hydroxylases, epoxide hydrolases (EHs), and flavin-containing monooxygenases (FMOs) are implicated in phase 1 reactions. Alcohol dehydrogenases (oxidoreductases) catalyse the oxidation of alcohols to aldehydes and ketones and aldehyde dehydrogenases catalyse the oxidation of aldehydes to carboxylic acids. Epoxide hydrolases catalyse the hydrolysis of epoxides to vicinal diols and play an important role in mitigating the carcinogenic mechanisms behind polycyclic aromatic hydrocarbons, which involve epoxides and flavin-containing monooxygenases oxygenate a wide range of foreign compounds, drugs, pesticides, and dietary-derived compounds (Zöllner et al, 2010). 

Furthermore, I mentioned what nutrients and dietary compounds support detoxification but additionally, it’s important to note that certain disease states have a negative impact on detoxification, such as infections, inflammation, and cancer, because the influx of pro-inflammatory cytokines, like IL-1, TNF- (tumour necrosis factor), and IL-6 can downregulate many drug-metabolising enzymes. Nutrients that promote detoxification also possess anti-inflammatory activity and it cannot be overstated that a protein-rich diet is essential for optimal detoxification (Novkovic, 2023).  

References

Cline, J.C. (2015). Nutritional aspects of detoxification in clinical practice. Alternative therapies in health and medicine, 21(3), 54-62. https://medpubresearch.com/research/Nutritional_Aspects_of_Detoxification_in_Clinical_Practice.pdf

Danielson, P.B. (2002). The cytochrome P450 superfamily: evolution and drug metabolism in humans. Current drug metabolism, 3(6), 561-597. https://www.researchgate.net/profile/Phillip-Danielson/publication/11089661_The_Cytochrome_P450_Superfamily_Biochemistry_Evolution_and_Drug_Metabolism_in_Humans/links/09e415084bd9110cf1000000/The-Cytochrome-P450-Superfamily-Biochemistry-Evolution-and-Drug-Metabolism-in-Humans.pdf

Hodges, R.E. & Minich, D.M. (2015). Modulation of metabolic detoxification pathways using foods and food-derived components: a scientific review with clinical application. Journal of nutrition and metabolism, 2015, 760689. https://doi.org/10.1155%2F2015%2F760689

Zöllner, A., Buchheit, D., Meyer, M.R., Maurer, H.H., et al. (2010). Production of human phase 1 and 2 metabolites by whole-cell biotransformation with recombinant microbes. Bioanalysis, 2(7), 1277-1290. https://doi.org/10.4155/bio.10.80

Novkovic, B. (2023, June 28). The science of detoxification: how phase 1 relates to health. SelfDecode. https://health.selfdecode.com/blog/the-science-of-detoxification/#:~:text=Phase%20I%20reactions%20include%20oxidation,of%20nicotine%20from%20cigarette%20smoke)