Detoxification Pathways: Phase I, Phase II and Elimination

Detox is one of the most widely marketed words in health. Juice cleanses, teas, foot pads, supplements and programmes promise to flush out toxins. Most of these products have no evidence that they remove anything. Yet the body does have remarkably sophisticated systems for transforming and eliminating foreign and endogenous compounds, systems that matter enormously in clinical practice, particularly for drug interactions, drug safety and understanding how nutrition and genetics influence response to medicines. This article describes those real pathways.

The purpose of biotransformation

Many compounds the body needs to eliminate are fat soluble: drugs, hormones, dietary chemicals, environmental pollutants and some metabolic products. Fat soluble compounds tend to be reabsorbed rather than excreted. Biotransformation converts them into water soluble forms that can be excreted in urine or bile. The liver is the main site, but the gut wall, kidneys, lungs and skin also contribute.

Phase I: functionalisation

Phase I reactions introduce or expose reactive chemical groups, typically through oxidation, reduction or hydrolysis. The most important enzymes are the cytochrome P450 family.

• CYP3A4 metabolises a large proportion of commonly used medicines.
• CYP2D6 metabolises many antidepressants, antipsychotics, beta blockers and opioids, and is highly variable between people.
• CYP2C9 and CYP2C19 metabolise warfarin, some anti inflammatory drugs, clopidogrel and proton pump inhibitors.
• CYP1A2 metabolises caffeine and some other drugs, and is induced by smoking.
• CYP2E1 metabolises alcohol and some solvents, and is induced by chronic alcohol use.

Phase I products can be more reactive than the original compound. Sometimes this activates a drug; sometimes it creates a toxic intermediate that must be quickly neutralised by phase II.

Phase II: conjugation

Phase II reactions attach water soluble molecules to compounds, preparing them for excretion.

A clinical example: paracetamol

Paracetamol illustrates how the phases work together. Most of a normal dose is conjugated by glucuronidation and sulphation and excreted safely. A small fraction is converted by phase I enzymes to a reactive metabolite, NAPQI, which is normally neutralised by glutathione. In overdose, the main pathways are saturated, more NAPQI forms, glutathione is depleted and liver injury follows. The antidote, N acetylcysteine, works by replenishing glutathione. Chronic heavy alcohol use, which induces CYP2E1 and depletes glutathione, and fasting or malnutrition, which reduce glutathione, increase vulnerability.

Phase III: transport and elimination

Transporter proteins move compounds into and out of cells, including efflux transporters such as P glycoprotein in the gut wall, liver and kidney. Conjugated compounds are excreted in bile, reaching the gut, or in urine through the kidneys. Some compounds excreted in bile are deconjugated by gut bacteria and reabsorbed, a process called enterohepatic recirculation, which affects the handling of some drugs and hormones.

What influences these pathways

Genetics

Genetic variation in drug metabolising enzymes explains much of the difference in drug response between people. Ultrarapid CYP2D6 metabolisers convert codeine to morphine unusually quickly; deaths in children after codeine led regulators to restrict its use in children. Poor CYP2C19 metabolisers activate clopidogrel less effectively. Pharmacogenomic testing is increasingly used to guide prescribing for specific drugs.

Medicines

Some medicines inhibit enzymes, raising levels of other drugs; others induce enzymes, lowering levels. St John’s wort is a potent inducer of CYP3A4 and P glycoprotein and reduces the effectiveness of many medicines, including oral contraceptives, some antiretrovirals, immunosuppressants and anticoagulants.

Foods

Grapefruit juice inhibits intestinal CYP3A4 and can markedly increase levels of some drugs, including certain statins, calcium channel blockers and immunosuppressants. Cruciferous vegetables contain compounds that can induce some phase I and phase II enzymes, and charcoal grilled meat induces CYP1A2. Smoking induces CYP1A2, and stopping smoking can raise levels of drugs such as clozapine.

Nutritional status

Phase II reactions require substrates derived from nutrition, including amino acids for glutathione and conjugation, and cofactors for methylation. Protein malnutrition and fasting reduce glutathione levels. However, there is no evidence that supplementing these substrates enhances detoxification in well nourished people.

Liver disease, age and pregnancy

Liver disease impairs biotransformation. Newborns and older adults have altered drug metabolism, and pregnancy changes the activity of several enzymes.

Detox products and programmes

A critical review of commercial detox diets found no compelling evidence that they eliminate toxins or produce lasting health benefits, and noted that products rarely identify which toxins they target or measure their removal. Some detox teas and herbal products contain laxatives or diuretics, and some herbal products have caused liver injury. Juice fasts may reduce protein intake and could reduce glutathione. The body’s own pathways, supported by adequate nutrition, liver and kidney health, avoidance of excess alcohol and reduction of unnecessary exposures, are the evidence based approach.

Clinical applications

1. Check interactions whenever patients take multiple medicines, supplements or herbal products, particularly St John’s wort and grapefruit.
2. Consider pharmacogenomics for drugs with established gene drug guidelines, especially where there has been treatment failure or unusual side effects.
3. Recognise vulnerability to paracetamol toxicity in heavy drinkers and people with poor nutrition.
4. Support liver health through weight management, alcohol reduction and treatment of fatty liver disease.
5. Ensure adequate protein and overall nutrition.
6. Discourage unproven detox products, and ask about them in patients with unexplained liver test abnormalities.

An illustrative case

A 34 year old woman taking an oral contraceptive and an immunosuppressant after a kidney transplant starts St John’s wort for low mood and a detox tea containing senna. Her immunosuppressant levels fall, and she has a breakthrough bleed. Her transplant team identifies the St John’s wort as the cause, stops it and adjusts her immunosuppressant, and her contraception is reviewed. The detox tea is stopped. Her low mood is treated with an approach chosen with her transplant team. Understanding biotransformation turned an apparently harmless herbal remedy into a recognised and preventable risk.

Real detoxification

The body’s biotransformation pathways are genuine, sophisticated and clinically important. They explain drug interactions, genetic differences in drug response and vulnerability to toxicity. Supporting them means protecting the liver and kidneys, maintaining good nutrition and avoiding unnecessary exposures, not buying products that promise to cleanse.