DAISY KAMENG BARUAHPhD Scholar

DEPARTMENT OF FOOD SCIENCE AND NUTRITION

XENOBIOTICS

INTRODUCTION

‘XENOBIOTICS’ are the foreign chemical substances found within an organism, which are not normally naturally produced by an organism or expected to be present within that organism. It can also cover substances which are present in much higher concentrations than are usual in any product.

TYPES OF XENOBIOTICS

Exogenous: Drugs Food additives Pollutants Insecticides Carcinogens

Endogenous: Bilirubin, Bile acids Steroids

SOURCES OF XENOBIOTICS

HUMAN EXPOSURE TO DIFFERENT XENOBIOTICS

Environ-mental xenobioticsToxic foodsDrugsCosmeticsOthersE. Donner (2015). Centre for

Environmental Risk Assessment and Remediation (CERAR)

I. ENVIRONMENTAL POLLUTION

Pesticides: Dimethoate 30 CPhosalone 35ECQuinalphos 25 EC

Chemicals: Carbon monoxideSulfur dioxideNitrogen oxides

RadiationsUV raysCosmic rays

Related diseases:

Lung Disease: AsthmaBlack lung disease (coal miners’ lungs) BronchitisAsbestosis (by breathing asbestos)Silicosis (among pottery workers exposed to silica

dust in clay)

Black lung disease

Reproductive Disorders:Infertility MiscarriageStillbirthBirth defects

Other related diseases: Carbon monoxide poisoningPneumoconiosis Radiation exposure defectsArsenic hands and feet

Shaw 2013

II. TOXIC FOODS Pesticides, herbicides, and growth hormones.

InfertilityUrinary tract infection

Food additives (MSG, artificial sweetners)Immidiate effects- Headache, altered concentrationLong term effects- Risk of cancer and CVD

Bisphenol A and surfactants.Hormonal ImbalanceMalabsoption syndrome

Heavy metals in waterArsenic hands and footTumours and cancers.

III. DRUGSAll drugs are not xenobiotics but drugs

such as antibiotics (Amikacin, Gentamycin, Sulphadiazine) are harmful to human.

Effects: Hypersensitivity: A set of undesirable

reactions produced by the normal immune system.

• Autoimmunity: An abnormal immune response of an organism against its own cells and tissues.

Allergies Atopic dermatitis

Rheumatoid arthritis Celiac sprue diseaseVitiligo

Infections: Invasion of an organism's body tissues by disease causing agents, their multiplication, and the reaction of host tissues to these organisms and the toxins they produce.

Lymphoproliferative disorder: A Condition in which lymphocytes are produced in excessive quantity.

Typically occur in people who have a weak immune system and prefer excess medication

IV. COSMETICSEffects of the ingredients present in beauty

products, can be more than just skin deep. Cosmetic industries who uses thousands of synthetic chemicals (xenobiotics) in its products right from lipstick and lotion to shampoo and shaving cream are harmful to the body.

A recent study done at University of Berkeley in California (2014) shows that many popular branded lipsticks (Lakme, Revlon, and Maybelline) have high

levels of aluminium, arsenic, lead, chromium and other heavy metals in them. According to Dr. Katharine

Hammond, these heavy metals can cause many health problems, if used for a long term.

Toxic chemicals present in cosmetics

Chemicals Product Possible causes

Phthalates Nail polish, perfumes Early puberty, Breast cancer, weak estrogen production

Triclosan Antibacterial soaps, deodrants toothpaste

Affects body’s immune system

1,4- dioxane

Shampoo, bodywash, children’s bath product

Carcinogenic

Parabens Creams, lotion, oinments, underarm deodrants, eye products

Breast cancer, vision defects, endocrine disruptor

Ethylene oxide

Shampoo’s and body wash Carcinogenic

1,3 butadiene

Shaving cream, sunscreen, foundations

Carcinogen exposed through inhalation

Lead Contaminant in over 650 cosmetic products like sunscreens foundation, nail polish, lipstick, whitening tooth paste

Neurotoxin linked to learning language and behavioural problems, miscarriage, reduced fertility, delays puberty.

Polycyclic aromatic hydrocarbons

Shampoo, lipstick Skin and breast cancer

National toxicology program , 2014

Adverse effects of cosmetics

V. XENOESTROGENA type of xenohormone that imitates endogenic

estrogen. They have estrogenic effects on a living organism even though they differ chemically from the endogenic estrogen produced by the endocrine system of any organism.

◦ Synthetic : Industrial compounds, such as Polychlorinated Bisphynol and phthalates.

◦ Natural : Plant and animal derived xenoestrogens (Dietary estrogen) Ex: Soyabean, red meat, milk products.

Mycoestrogens/mycotoxins(estrogenic substances from fungi)

Affects : InfertilityEndometriosisDysmenorrhoeaDysfunctional uterine bleedingAdenomyosis

Effects: Phytoestrogens/ dietary estrogen are occcasionaly used as natural HRT (hormone replacement therapy) during postmenopausal period.

Xenobiotic and human immune system

IMMUNOTOXICITY

Immunosupression

Hypersensitivity

Immunostimulation

Autoimmunity

Xenobiotics may interact with cellular immune system which results in altered immune status which may lead to immunotoxicity

Realm of xenobiotic activity in immune system

Xenobiotics

Xenobiotic related health

hazardsAutoimmunity/Hypersensitivity

Immune alteration

Oxygen free radical

generationMay act as

antigen

Direct effect on immune system

resulting in suppression and

stimulation

Indirect exerted modulation through hormonal imbalance

Effect on humoral immune

response

Effect on cell mediateda immune response

Altered suceptibility to

pathogens Rao and Richardson 1999

IgE-Mediated Hypersensitivity to xenobiotics

Banerjee et al., 2008

CHARACTERISTICS OF XENOBIOTICS

Most xenobiotics are: Lipophillic Penetrate membranes by

diffusion Transported by lipoproteins in

blood Require chemical conversion to

facilitate excretion

ENTRANCE, DISTRBUTION AND STORAGE OF XENOBIOTICS

Entrance to the body:

Ingestion ; Oral Food contaminants

Gastrointestinal absorption Inhalation ; Nasal cavities Air pollutants

Pulmonary absorption Skin ; Epidermis, dermis Toxic chemicals

Dermal penetrationOther routs; injection, conjunctival instillation, suppositories

Distribution and storage: Xenobiotics are distributed through peripheral tissues

via blood, lymph, cerebrospinal fluid (CSF) and than stored in:

Liver: Food contaminants ( MSG, lead, Mycotoxins)Drug deposites (Tetracycline, Doxycycline)

Body fat: Pesticides (Dimethoate 30C, Phosalone 35EC, Quinalphos

25EC)Organophosphate compounds (Plasticizers,herbicides,

insecticide)DTT

Bone: FluorideLeadCadmiumRadiumPlutonium

FATE OF XENOBIOTICSXenobiotics

Entrance to body

Ingestion Inhalation

Dermal penetration

Absorption into blood streamand

Distribution to body tissues and organs

Biotransformation

Conjugation

Toxicity

action

• Pharmacologic • Cell injury• Immunologic• Carcinogenic

Storage

Outside body

Inside body

Outside bodyExcretion

METABOLISM OF XENOBIOTICS

Till date more than 200,000 xenobiotics have been identified, most of which are metabolized in the human body (mainly in liver).

Understanding how xenobiotics are handled at the cellular level is important for learning how to cope with the chemical onslaught (attack).

PHASE IBIOTRANSFORMATION OF XENOBIOTICS

Biotransformation is the metabolic modification of the molecular structure of a compound, resulting in the loss or alteration of some characteristic properties of the original compound. It effects the solubility, mobility and toxicity of the organic compound.

Xenobiotics are biotransformed through any of the following reactions:

Oxidation (Drugs, heavy matels) Reduction (Cosmetic chemicals, heavy metals) Hydrolysis (Drugs)

(Parkinson A.2012)

OXIDATIONOxidation of xenobiotic are carried out by a

xenobiotic biotransforming enzyme which play an important role in the solubility and mobility of toxic producing molecules in its major site- LIVER.

Cytochrome P450 enzyme

Parkinson A (2013) studied that cytochrome P450 enzyme convert excess steroid hormones to water-

soluble metabolites that are excreted in urine or bile

REDUCTIONCertain xenobiotics containing

aldehyde ketone, disulfide, sulfoxide, quinone, azo, or nitro groups are often reduced enzymatically or nonenzymatically by interaction with some reducing agents: Xenobiotics Reducing

agentsSite

Parabens FAD Liver, skinLead FAD, FMN Intestinal

microfloraPthalates FMN EpidermisArsenic NADP, FMN Liver, Intestinal

microflora

HYDROLYSISThis reaction involves the breakdown

of any bond in a molecule using water. Biotransformation of xenobiotics through hydrolysis is done by certain hydrolytic enzymes.

Xenobiotics Hydrolytic enzyme

Site

Drugs

Procain Esterase Liver tissues, cystol

Procanamide Peptidase Endoplasmic reticulum cystol

Spironolactone Epoxide hydrolase

Mitochondria

Diisopropylfluorophosphate (DFP)

Esterase Endoplasmic reticulum

PHASE II CONJUGATION

The end products found from phase I reaction is combined with some highly water soluble endogenous metabolites such as:

Glucuronic acid Sulphate Glycine

This renders them even more water-soluble, and are eventually excreted through urine or bile.

Conjugation with glucoronic acid

Conjugation with sulphate

Conjugation with glycine

EXCRETION OF XENOBIOTICS

Urinary excretion

Biliary (fecal) excretion

Exhalation

Other secretionsSalivaSweatBreast milk

Excretion via mammary routeSince milk is an emulsion in aqueous protein solution, a variety of metabolites (both polar and non-polar) can be excreted via this route.- High polar metabolites such as alcohol, caffeine- Medium polar compounds such as certain drugs- Low polar or lipid-soluble compounds such as pesticides/insecticides and industrial chemicals

An epidemiological survey in Lombardy (Northern Italy) studied about presence of xenobiotics- aflatoxins, ochratoxin A, lead and cadmium in human milk and confirmed the presence of ochratoxin A (85.7% ), lead (75.7% ), cadmium (87.4%) and aflatoxin (72%) in human milk samples.

Patriarca M, Menditto A, Rossi B, Lyon TDB, Fell GS (2014) Environmental exposure to metals of newborns, infants and young children. Microchemical Journal-

CATEGORIES OF METABOLIZERS OF XENOBIOTICS

Every human differs (more or less) in xenobiotics metabolism depending on their metabolic activity. Three major categories of metabolizers are classified as:

Extensive metabolizer – Normal enzyme activity.

Poor metabolizer - No or less enzyme activity

Very poor metabolizer - Decreased metabolism of xenobiotics, needs

medication or therapies

FACTORS AFFECTING METABOLISM OF XENOBIOTICS

Age: Metabolic activity tends to decrease with increase in age.

Nutritional status: Poor nutritional status affects enzyme activity in the liver.

Enterohepatic circulation Pathological status: Liver diseases also affects

metabolic activity in the body. Hepatoma Jaundice Hapatitis Cirrosis Wilson’s disease

DETOXIFICATIONA natural health recovery approach, used by

traditional herbalists, naturopaths and nutritionally trained chiropractors.

It is a specific active metabolic pathway throughout the human body, that processes unwanted chemicals for elimination. This pathway involves a series of enzymatic reactions that neutralize and solubilise toxins, and transport them to secretory organs (like the liver or kidneys), so that they can be excreted from the body.

Detoxification usually includes one or more of the following: ◦ Colon cleansing◦ Chelating therapy◦ Detox foods

◦ COLON CLEANSING: A type of colon therapy which encompasses a number of alternative medical therapies, claimed to remove "toxins" from the colon and intestinal tract. Colon cleansing may also be branded as colon hydrotherapy or colonic irrigation.

EnemasLaxativesHerbal therapiesEnzymes

Herbs used in colon cleansing

FLEX SEED, protects gut and intestinal flora

ALFA ALFA, soothes digestive tract during cleanse

SPIRULINA, boosts oxygen and eliminate toxins

ALOE VERA, heals and soothes intestinal lining

YOGHURT, Excellent source of probiotics

MANGO, relieves constipation with its laxative properties

PEPPERMINT, alleviates the intestine after cleanse

FENNEL SEEDS, relieves lower abdominal pain and enhance digestion

◦ CHELATING THERAPY: Chemical process in which a synthetic solution; EDTA (ethylenediaminetetraacetic acid) is injected into the bloodstream to remove heavy metals or minerals from the body.

It is used as a treatment for metal poisoning like:

Acute mercuryIronArsenicLeadUraniumPlutonium

The chelating agent may be administered intravenously intramuscularly or orally, depending on the agent and the type of poisoning

1900’s

DETOX DIET

Water and water based drinks are one of the simplest detox diets around.

Calcium-ions and magnesium found in hard water helps to remove harmful toxins from our body.

It helps to promote a healthy carbohydrate metabolism by burning calories fast.

WATER

Watermelon-lime-mint with water drink:

Watermelon, flush out toxins, due to presence of organic compound citrulline, which helps our liver and kidneys to filter and get rid of ammonia.

lime juice, stimulate and regulate our digestive track, it thins out bile, which allows it to flow more freely.

Mint leaves, with refreshing flavor helps to digest even more effectively, improving the flow of bile from the liver to gallbladder then to small intestine, where it breaks down the unwanted dietary fats.

Water based drinks:

Apple cinnamon detox drink: Zero Calorie detox water. Stimulates and cleanse our internal organs.

Water, honey and cinnamon detox drink:Detoxify body.Aids in weight loss.

Global healing centre 2015

Recent studies proved that rats fed at a diet containing honey gained less weight compared to rats fed with a diet rich in

sugar.

CRUCIFEROUS VEGETABLES & LEAFY GREENS:

gluc

osin

olat

e

Antio

xida

nts

Neutralize toxic metals

Mild diuretic

Consumed as : green detox drinks smoothies

FRUITS

Avocado, helps our body to produce certain antioxidants and glutathione, which our liver needs to filter properly.

Papaya, contains papain similar to other types of enzymes in the pancreas which helps to digest protein. But, those enzymes need acid for activation and papain can work even without the presence of acid.

Grapefruit: It is high in antioxidants and vitamin C. grapefruit juice aids the liver in flushing carcinogens and pesticides out of the body.

Indian gooseberry: Elimination of toxins relies on healthy circulation, digestion, and elimination, and amla supports all three of these functions with its rich antioxidant content.

Pomegranate: Pomegranate boosts as a natural detoxifier as these are packed with healthy and healing antioxidants, flavonoids and polyphenols.

SUPPLEMENTS FOR REDUCING AND ELIMINATING XENOBIOTICS

N-acetyl cysteine is a precursor to one of the body’s most effective antioxidants – glutathione.

Green tea extract, quercetin, and alpha lipoic acid are powerful antioxidants that assist in xenobiotic metabolism.

B vitamins, vitamin C, and vitamin E are cofactors in metabolic processes that eliminate xenobiotics.

Calcium -gluconate assists in the metabolism and removal of xenobiotics and xenoestrogens.

Human health specialist, 2015

TIPS TO AVOID EXPOSURE OF XENOBIOTICS

Avoid all artificial colours, flavours, preservatives and sweeteners.

Eat minimum processed foods; the closer a food is to its natural state, the lower the toxin risk.

Eat organically grown food whenever possible,. Carefully select body-care products, avoiding

petroleum-based cosmetics. Avoid using chemical-based household cleaners,

laundry products and air fresheners. Toxin-free, biodegradable products made with natural ingredients should be prefered.

Drink filtered or purified water.

FIVE WAYS TO REDUCE EXPOSURE TO XENOBIOTICS

• Say “No” to plastic◦PVC; commonly found in condiment and salad dressing

bottles, and cheep baby toys.◦Used in Styrofoam coffee cups and containers.◦Unless it specifically states “BPA-free”.• Wash your produce

Fruits or vegetables, contaminated with pesticides, herbicides, and pathogenic microorganisms should be washed thoroughly.• Pregnant Mothers should consult her physician before

taking any supplements• Be volatile organic compounds (VOCs) free:

New paint, furnishings, and carpeting etc are some of the major xenobiotic sources.

• Wise selection of cosmetics:

CONCLUSION Prevention and cure of adverse health effects

caused by exposure to xenobiotics must be an integral part of protecting public health. The ever increasing quantity and variety of chemical compounds to which the public is inevitably exposed to, makes it obvious for effective evaluation of health effects caused due to these chemical mixtures. The classical toxicological methods only focus on the toxicity of individual chemicals. Hence In-depth mechanistic animal studies and rationally designed clinical trials should be done to find the modulating effects of food enzymes for detoxification.

We cannot free ourselves and the environment from the toxic effects of xenobiotics but we can atleast try our

best to avoid them with proper lifestyle and good food.

“STAY WELL AND BE HEALTHY”