Liver function

Source of toxins in the body

• Xenobiotics– Environmental chemicals– food chemicals or contaminant– drug– infectious organism

• endogenous– metabolism e.g. steroid hormones, bile acids– endogenous toxins, e.g.abnormal metabolism,

disease state

Conditions caused or exacerbated by toxin overload

– CFS

– immune deficienty

– chronic inflammatory disorders

– allergies

– autoimmune disease

– chemical sensitivities

– cancer

– Liver damage, kidney damage, etc.

– leaky gut syndrome (GIT wall damage, permeated via food allergy or alcohol)

– almost any chronic disease process

The bodies protective mechanism against toxins in body fluid

• Storage in adipose tissue

• elimination via kidneys, lungs, without any further processing

• elimination via urine, bile, after biotransformation by the liver

Biotransformation of toxins by the liver

• Purpose is to make it easier for the toxin to be excreted.

• Two reactions– phase I reactions – phase II reactions

Phase I

– Involving oxidation or reduction reactions.– Dependent on enzymes associated with smooth

endoplasmic reticulum (ie microsomes) known as the mixed function oxidase system (involves a hemoprotein known as cytochrome P450)

– generally involves exposing or adding a functional group, usually oxygen, by free radical mechanism.

– Involves the generation of free radicals.

Bioactivation – Can result in the production of more toxic

compounds, esp. for xenobiotics, which is called bioactivation, which can lead to;

• tissue damage (e.g. hepatotoxicity, teratogenicity

• react with phase II enzymes, made harmless and excreted

• react with a cell protein forming and antigen, which may lead to immunological reactions such as drug-induced lupus.

• Bind with DNA causing mutations which can lead to cancer (many carcinogens are first activated by hepatic microsomes.

Enzyme induction

• Both phase I and II enzyme can be induced ie increased production of enzymes via new protein synthesis

• inducing the the cytochrome P450 enzymes occur after chronic exposure to ethanol, some drugs, pesticides, smoking.

• Some 50-100 enzymes make up th P450 system.

• Phase I directly neutralise some chemicals,

• the activity of the enzymes varies between persons, eg chemical workers in Turin, or smokers, some get cancer other do not.

Underactive phase I

• Experience caffeine intolerance, intolerance to perfumes, other environmental chemicals, increase risk of liver disease.

Overactive phase I

• Relatively unaffected by caffeine.

• Metabolisation by phase I lead;– to transformation of less toxic form, – transforming to make it water soluble and then

excreted via the kidneys– converting the toxin to more chemically active

form, so making it more chemically reactive, so more easily metabolised by the phase II enzymes

– Caffeine is directly neutralised by phase I.

Free radicals

• For each molecule of toxin metabolised by phase I , one molecule of free radical is generated. Without adequate free radical defenses, every time the liver neutralises a toxin exposure, it is damaged by the free radical produced.

Antioxidant

• Most important one in the liver is glutathione, in the process of neutralising free radicals, glutathione is oxidised to glutathione disulfide. Glutathione is required for one of the key phase II detoxification processes, when high levels of toxins can lead to glutothione depletion, and phase II can not occur.

• Phase I must be balance by phase II other wise backlog problem. – Eg if very active phase I and slow II, usually

people suffere severe toxic reactions to environmental toxins.

– Large amount of toxin, lead to high activity phase I, leading to build up.

Substances that activate phase I detoxification

• Drugs; alcohol, nicotine, phenobarbital, sulfonamides, steroids.

• Foods; cabbage, broccoli, sprouts (also stimulate phase II -indole-3-carbinol-) Charcoal broiled meats, high protein diet, oranges and tangerines (the last two also stimulate phase II, -limonene-).

• Nutrients; niacin, vitamin B1,C

• herbs; caraway, dill seeds, hypericum perforatum.

• Environmental toxin; exhaust fumes, paint fumes pesticides, dioxin.

Inhibitors of phase I detoxification

• Drugs; benzodiazepin, antihistamines, cimetidine and other antacids, ketoconazole, sulphaphenazole.

• Foods; grapefruit, turmeric, red chili pepper, clove, onions, marigold.

• Other; aging (plus also generally reduced blood flow through the liver,lack of physical activity, poor nutrition, toxins from inappropriate bacteria in the intestines.

Phase II

• Involves conjugation; attaching small chemicals to the toxin, which neutralises the toxin, or makes it more easily excreted through the urine or bile.

• Some toxins the phase II enzymes act directly, others have to be activated by phase I enzymes.

Phase II detoxification pathways

• Glutathione conjugation

• amino acid conjugation

• methylation

• sulfation

• acetylation

• glucuronidation

Glutathione conjugation• Detoxifies

• acetaminophen, nicotine, insectisides, epoxides(carcinogens)

• nutrients needed; glutathione, B6

• activators• brassical family, limonene foods

• inhibitors; • def. of Vit.B2, glutathione, selenium, zinc

• clinical indication of dysfunction• chronic chemical exposure, chronic alc. consumption

Deficiency glutathione

• Induced by diseases that increase the need of glutathione,

• or deficiencies of nutrients

• or diseases that inhibit its formation; pulmonary fibrosis, adult respiratory distress syndrome, HIV, heptic cirrhosis, cataract formation, due to increased need of glutathione. Also smoking.

Glutathione

• Diet; fresh fruits, vegetables, cooked fish and meat.

• Vit C increases synthesis of glutathione. 500mg a day is enough.

Schisandra chinensis

• Enhances hepatic glutathione status, and induces phase I activity.

• Gomisin A; stimulates liver regeneration, prevents acetaminophgen toxicity, as does schisandra, improves bile acid metabolism (Phase II), increases glutothione S-transferase.

• Does not cause harmful bioactivation• dose; 2-3 g per day.

Carduus marianus• Increases the synthesis of glutathione, by

about 35%.

• Increase the rate of tissue regeneration

• powerful antioxidant, many times more than Vit. C and E.

• also inducer of phase I enzymes.

• Shown to protective against several liver toxic chemicals, its key component is the prevention of depletion of glutathione by alcohol or other toxic chemicals.

Brassicas (cruciferous)

• Brussels sprouts, broccoli, cabbage, horseradish, mustard, nasturtium, watercress,.. Contain sulfer glucosides know as glucosinolates.

• Upon cooking, grating, digestion,steam distillation; converted to isothiocyanates which also contain sulfer.

• Most potent inducer of phase II enzymes.

• Anticancer and cancer preventing activities.

• Research shown that 30 g of brussel sprouts per day increase glutathione levels in liver and small intestines by 40-50% in males, not significant increase in females.

Rosemarinus off. And Salvia off.• Carnasol; antioxidant, induces glutothione,

and NAD(P)H:quinone reductase (important phase II enzymes.

Parsey leaf

• Myristicin; inducer of glutathione activity

Citrus fruit oils

• Increases glutathione activity

Amino acid conjugation

• Detoxifies; benzoate, aspirin• nutrients needed; glycine• activators; glycine• inhibitors; low protein diet• clinical indicators of dysfunction; intestinal

toxicity, toxemia, hepatitis, chronic arthritis, hypothyroidism, chemical exposure, liver disorders, carcinomas.

Methylation

• Detoxifies; estrogen, dopamine, ephinephrine, histamine, thiouracil

• nutrient needed; S-adenosylmethionine• activators; lipotropic nutrients (choline and

methionine, betaine, folic acid, B12• inhibitors; def. Folic acid or B12• clinical indicators of dysfuncition; PMS.

Estrogen excess, cholestasis, OCP use.

Taraxacum officinalis

• Contains choline, also Vit.A,B,C,D,iron, silicon, Mg,K,Zc,Mang,Phosphorus, flavonoid glycosides.

• Enhances the flow of bile• correct liver imbalances• lipotropic effect; useful for PMS, estrogen

excess.• Anti cancer (breast cancer)

Sulfation • Detoxifies;

– several food additives, toxins from intestinal bacteria, and environment, several neurotransmitters, aniline dyes, coumarin, acetamoinphen, methyl-dopa, estrogen, testoterone, thyroxin

• nutrients needed; – cysteine, methionine, molybdenum

• activators; cystein, methionine, taurine• inhibitors;

– tartrazine dye, NSAID eg aspirin, molybdenum defeciency. Excess molybdenum, B6 (over 100mg per day)

• Clinical indicators of dysfunction; – intestinal toxicity, parkinsons, alzheimer, RA

Acetylation

• Detoxifies; sulfonamide, mescaline

• nutrients needed; acetyl-CoA

• inhibitors; B2,B5, or C def.

glucuronidation

• Detoxifies; – acetaminophen, morphine, diazepam, digitalis, aspirin, vanillin,

benzoates, menthol and some hormones.

• Nutrients needed; glucuronic acid

• activators; – fish oils, limonene containing foods, OCP, smoking, phenobarbital

• inhibitor; aspirin, probenecid

• clinical indication of dysfunction; – gilbert syndrome, yellow discoloration of eyes and skin, not due to

hepatitis.

Sulfoxidation

• Is the process by which sulfur containing molecules in drugs and foods (garlic) are metabolised. And a process by which the body eliminates food additives used to preserve many foods.

• The enzyme sulfite oxidase metabolises sulfite to safer sulfates, which are excreted in the urine, if poorly function an increased ration of sulfite to sulfate in urine.

• Detoxifies; sulfite, garlic compounds

• nutrients needed; molybdenum

• activator; molybdenum

• clinical indicator of dysfunction; adverse reaction to sulfer containing foods, asparagus resulting in strong odour.

• Strong odour after eating asparagus, genetic variability in detoxification via sulfoxidation.

• Poorly functioning; sensitive to sulfer containing foods and drugs.

Turmeric (Curcuma longa)

• Hepatoprotective against several toxins due to antioxidant activity; chemopreventative of carcinogenesis

• increase in phase II enzyems, and decreases some phaseI activity

• reduces excretion of urinary mutagens in smokers.

Camelia sinensis

• Polyphenolic compounds; pronounced chemopreventative activity against carcinogenesis and increase Phase I and Phase II activity.

• Found to prevent damaging effect of smoking.

• Also effecton increasing glutathione levels.

• Dose; 1;1 5 - 14 ML PER DAY

Bile excretion

• One of the primary routes for the elimination of modified toxins is through bile. 2 pints each day.

• If inhibited, toxins stay in the liver longer.

• Ie cholestasis.

• Associated with alteration of liver funcions test.

• Bile is a carrier for toxic substances, bringing them to the intestines, where the bile and toxic load are absorbed by fiber and excreted.

• Low fibre diet; reabsorption of toxins.

• Bacteria modify toxins to more damaging forms.

Cholestasis causes

• Gallstones• alcohol• endotoxins• hereditary disorders• viral hepatits• hyperthyroidism or

thyroxin• pregnancy

• Chemicals; natural and synthetic hormones