Phase 1 And 2 Liver Detoxification Pathways
Inside the liver cells there are sophisticated mechanisms that have evolved over millions of years to break down toxic substances. Every drug, artificial chemical, pesticide and hormone, is broken down (metabolised) by enzyme pathways inside the liver cells.
Many of the toxic chemicals that enter the body are fat-soluble, which means they dissolve only in fatty or oily solutions and not in water. This makes them difficult for the body to excrete. Fat soluble chemicals have a high affinity for fat tissues and cell membranes, which are made of fatty substances. In these fatty parts of the body, toxins may be stored for years, being released during times of exercise, stress or fasting. During the release of these toxins, symptoms such as headaches, poor memory, stomach pain, nausea, fatigue, dizziness and palpitations may occur. The body's primary defence against metabolic poisoning is carried out by the liver.
The liver has two mechanisms designed to convert fat-soluble chemicals into water soluble chemicals so that they may then be easily excreted from the body via watery fluids such as bile and urine.
How the Liver Detoxifies
There are two major detoxification pathways inside the liver cells, which are called the Phase 1 and Phase 2 detoxification pathways.
- metabolic end products
- micro organisms
- food additives
Phase One - Detoxification Pathway
Phase one detoxification consists of oxidation reduction and hydrolysis. Phase one detoxification is catalysed by enzymes referred to as the cytochrome P450 enzyme group or Mixed Function Oxidase enzymes MFO. These enzymes reside on the membrane system of the liver cells (called Hepatocytes). Human liver cells possess the genetic code for many isoenzymes of P-450 whose synthesis can be induced upon exposure to specific chemicals. This provides a mechanism of protection from a wide variety of toxic chemicals.
To put it simply, this pathway converts a toxic chemical into a less harmful chemical. This is achieved by various chemical reactions (such as oxidation, reduction and hydrolysis), and during this process free radicals are produced which, if excessive, can damage the liver cells. Antioxidants (such as vitamin C and E and natural carotenoids) reduce the damage caused by these free radicals. If antioxidants are lacking and toxin exposure is high, toxic chemicals become far more dangerous.
Some may be converted from relatively harmless substances into potentially carcinogenic substances. Excessive amounts of toxic chemicals such as pesticides can disrupt the P-450 enzyme system by causing over activity or what is called 'induction' of this pathway. This will result in high levels of damaging free radicals being produced. The danger is if these reactive molecules are not further metabolised by Phase II conjugation, they may cause damage to proteins, RNA, and DNA within the cell.
Substances that may cause overactivity (or induction) of the P- 450 enzymes
- Saturated fats
- Organophosphorus pesticides
- Paint fumes
- Exhaust fumes
The family of P-450 enzyme systems is quite diverse, with specific enzyme systems being inducible by particular drugs, toxins or metabolites. It is this characteristic that has allowed the development of special tests to check the function of the various pathways.
The Substrates (the substance acted upon by the enzyme) of cytochrome P-450 enzymes.
- dextrometh- orphan
- oxicam drugs
Cofactors of P450 Phase 1 detoxification
NADH, riboflavin, niacin, magnesium, iron, certain indoles from cruciferous vegetables.
Substances that inhibit cytochrome P450
Many substances inhibit cytochrome P450. This situation can cause substantial problems as it makes toxins potentially more damaging because they remain in the body longer before detoxification.
Grapefruit juice decreases the rate of elimination of drugs from the blood and has been found to substantially alter their clinical activity and toxicity. Eight ounces of grapefruit juice contains enough of the flavonoid naringenin to decrease cytochrome P450 activity by a remarkable 30%.
Curcumin, the compound that gives turmeric its yellow colour, is interesting because it inhibits phase I while stimulating phase II. This effect can be very useful in preventing certain types of cancer. Curcumin has been found to inhibit carcinogens, such as benzopyrene (found in grilled meat), from inducing cancer in several animal models. It appears that the curcumin exerts its anti-carcinogenic activity by lowering the activation of carcinogens while increasing the detoxification of those that are activated. Curcumin has also been shown to directly inhibit the growth of cancer cells. As most of the cancer-inducing chemicals in cigarette smoke are only carcinogenic during the period between activation by phase I and final detoxification by phase II, curcumin in the turmeric can help prevent the cancer-causing effects of tobacco.
Phase I detoxification and ageing
The activity of phase I detoxification enzymes decreases in old age. Aging also decreases blood flow through the liver, further aggravating the problem. Lack of the physical activity necessary for good circulation, combined with the poor nutrition commonly seen in the elderly, add up to a significant impairment of detoxification capacity, which is typically found in ageing individuals.
Phase Two - Detoxification Pathway
This is called the conjugation pathway, whereby the liver cells add another substance (eg. cysteine, glycine or a sulphur molecule) to a toxic chemical or drug, to render it less harmful. This makes the toxin or drug water-soluble, so it can then be excreted from the body via watery fluids such as bile or urine.
Major Phase II pathways
- Glucuronide conjugations
Through conjugation, the liver is able to turn drugs, hormones and various toxins into water soluble excretable substances. Individual xenobiotics and metabolites usually follow one or two distinct pathways. This makes testing of the various pathways possible by challenging with known substances.
Sulphur containing foods and amino acids stimulate phase II detoxification
For efficient phase two detoxification, the liver cells require sulphur-containing amino acids such as taurine and cysteine. The nutrients glycine, glutamine, choline and inositol are also required for efficient phase two detoxification.
Eggs and cruciferous vegetables (eg. broccoli, cabbage, Brussels sprouts, cauliflower), raw garlic, onions, leeks and shallots are all good sources of natural sulphur compounds to enhance phase two detoxification. Thus, these foods can be considered to have a cleansing action.
The phase two enzyme systems include both UDP-glucuronyl transferase (GT) and glutathione-S-transferase (GSH-T).
Glutathione-S-transferase is the most powerful internal antioxidant and liver protector. It can be depleted by large amounts of toxins and/or drugs passing through the liver, as well as starvation or fasting. Phase II reactions may follow Phase I for some molecules or act directly on the toxin or metabolite.
Substrates of the glycine pathway
Salicylates and benzoates are detoxified primarily through glycination. Benzoate is present in many food substances and is widely used as a food preservative. Many other substances are detoxified as well via the glycine conjugation pathway. Patients suffering from xenobiotic overloads and environmental toxicity may not have sufficient amounts of glycine to cope with the amount of toxins they are carrying.
Substrates of the sulphation pathways
Neurotransmitters, steroid hormones, certain drugs such as Acetaminophen (also known as paracetamol) and many xenobiotic and phenolic compounds.
Substrates of glucuronidation
Polycyclic aromatic hydrocarbons, steroid hormones, some nitrosamines, heterocyclic amines, some fungal toxins, and aromatic amines. It also removes "used" hormones, such as oestrogen and T4 (thyroid hormone) that are produced naturally by the body.
If the phase one and two detoxification pathways become overloaded, there will be a build up of toxins in the body. Many of these toxins are fat soluble and incorporate themselves into fatty parts of the body where they may stay for years, if not for a lifetime. The brain and the endocrine (hormonal) glands are fatty organs, and are common sites for fat-soluble toxins to accumulate. This may result in symptoms of brain dysfunction and hormonal imbalances, such as infertility, breast pain, menstrual disturbances, adrenal gland exhaustion and early menopause. Many of these chemicals (eg. pesticides, petrochemicals) are carcinogenic and have been implicated in the rising incidence of many cancers.
Bitter herbs to improve phase 1 and 2 detoxification
Bitter herbs are the corner stone of herbal medicine. A range of physiological responses occur following stimulation of the bitter receptors of the tongue. The bitter taste stimulates the specific bitter taste buds at the back of the tongue to stimulate the parasympathetic nervous system to trigger a number of reflexes. These reflexes are important to the digestive process and general health.
Specifically in relation to digestion herbal bitters;
Sialogogues – stimulate saliva to digest carbohydrates.
Orexogenics – stimulate hydrochloric acid to digest protein.
Chologogues – Stimulate bile flow to digest fats.
The stimulation of the flow of digestive juices from the exocrine glands of mouth, stomach, pancreas, duodenum and liver, aid in digestion, absorption and assimilation of foods and nutrients. There is also a very mild stimulation of endocrine activities, especially insulin and glucagon secretion by the Islets of Langerhans in the pancreas therefore used to treat of non-insulin dependent diabetes. By promoting the flow of bile, bitters assists the liver in its detoxifying capacity.
Carina is available to lecture for your group or organisation on this subject
Carina Harkin BHSc.Nat.BHSc.Hom.BHSc.Acu. is a practitioner of 11 years, complementary medicine lecturer of 4 years and mother of six in Galway, Ireland who practices what she teaches.
For an appointment call Carina directly on 083 34 66 333.
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