degradation of xenobiotics

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XENOBIOTICS

Guided By:Dr.K.S.ChandrashekharaiahAssociate ProfessorDept. of Biochemistry

Seminarian:Ganesh Prasad D.N.ll M.Sc. Biochemistry

INTRODUCTION

Xenobiotics are chemicals not naturallybelonging to or originating from a particularorganism or an ecosystem.

The term Xenobiotic derived from the GK word “Xenos=Foreigner or Stranger”

The body removes xenobiotics by xenobiotic metabolism. This consists of the deactivation and the excretion of xenobiotics and it happens mostly in the liver.

Xenobiotics • Food additives, poisons, toxins, certain drugs,

chemicals, environmental pollutants, pesticides and other foreign substances.

Xenobiotics

Xenobiotics can be-

a) Exogenous - The foreign molecules which are not

normally ingested or utilized by the organism but they

gain entry through dietary food stuffs, or in the form of

certain medicines/ drugs used for a therapeutic cause

or are inhaled through environment .

Examples- Drugs, food additives, pollutants,

insecticides, chemical carcinogens etc.

Xenobiotics can be-

b) Endogenous – Though they are not foreign substances

but have effects similar to exogenous xenobiotics. These

are synthesized in the body or are produced as

metabolites of various processes in the body.

Examples-Bilirubin, Bile acids, Steroids, Eicosanoids and

certain fatty acids.

Source of xenobiotic compounds

1. Petrochemical industry : oil/gas industry, refineries, and the production of basic chemicals e.g. vinyl chloride and benzene2. Plastic industry :

- closely related to the petrochemical industry- uses a number of complex organic compounds such as anti-oxidants, plasticizers, cross-linking agents

3. Pesticide industry : most commonly found central

structures are benzene and benzene derivatives,

often chlorinated and often heterocyclic

4. Paint industry : major ingredient are solvents,

xylene, toluene, methyl ethyl ketone, methyl

isobutyl ketone and preservatives

5. Others : Electronic industry, Textile industry, Pulp

and Paper industry, Cosmetics and Pharmaceutical

industry, Wood preservation

Effects of Xenobiotics

Food Chain Effects Bioaccumulation

• Primary producers and lower trophic level organisms take up PCBs, accumulates in the food chain

• Higher organisms eating primary producers get more concentrated amounts of toxin

Often people consuming higher organisms are exposed to more toxic forms than factory workers

Human Health

• carcinogenous: – Liver cancer – melanoma

• immune system– suppressed – swollen thymus gland

in infants

• reproductive system – reduced birth weight– decrease in gestational

ages– Abortions

Human Health Cont.

• nervous system– infant neurological

functions– short-term memory– Learning

• endocrine system– thyroid health

• other health effects

Marine and Animal Health• Inhibits plankton growth

and photosynthesis affecting the food chain– reduce trophic pathways

• Reduce plankton size• Reduce size of higher

feeders• Divert carbon flow to non-

harvestable species– less plankton = less bigger

food fish

• Toxic to crustaceans, mollusks, and fish at concentrations of only a few ppb

DETOXIFICATION OF XENOBIOTICS

Phases of Detoxification Processes

Phase I Phase II

Oxidation AlcoholAldehydes

AminesDrugs

Ethanol → Acetic acid

Methanol → Formic acid

Benzaldehyde → Benzoic acid

Aliphatic amine → Aliphatic acid + Urea

Oxidation

Most of the oxidation reactions are catalysed by monooxygenase or cytochrom P450

Many reactions of cytochrome P450 involve

the addition of a hydroxyl group to xenobiotics

Hydroxylation

HydroxylationThe

responsible enzymes are

called monooxygen

asesor

cytochrome P450

Cytochrome P450

Hydroxylation

Reduction

It is less common and less important than oxidation.

Hydrolysis Many drugs are detoxified by hydrolysis.

Conjugation Glucuronic acid

Glutathione Sulfate Glycine

Conjugation means the chemical combination of one

compound with another compound.

Conjugation with Glucuronic acid

Benzoic acid + UDP-Glucuronic acid → Benzoyl glucuronide + UDP

Paracetamol + UDP-Glucuronic acid → Conjugated product + UDP

Diclofenac sodium + UDP-Glucuronic acid → Conjugated product + UDP

Conjugation with Glycine

Conjugation with Glutathione

Conjugation with sulfate

Biodegradation of Petroleum compounds

Petroleum compounds are categorized into 2 groups• Aliphatic hydrocarbon e.g. alkane, alcohol,

aldehyde • Aromatic hydrocarbon e.g. benzene, phenol,

toluene, catechol

• H.C. (substrate) + O2 H.C.-OH + H2O

• H.C. (substrate) + O2 H.C.29

monooxygenase

dioxygenase

Compound Organisms

Naphthalene Acinetobacter calcoaceticus , Alcaligenes denitrificans,Mycobacterium sp. , Pseudomonas sp., Pseudomonas putida , Pseudomonas fluorescens , Pseudomonas paucimobilis , Pseudomonas vesicularis , Pseudomonas cepacia , Pseudomonas testosteroni , Rhodococcus sp. , Corynebacterium renale , Moraxella sp., Bacillus cereus , Streptomyces sp.

Acenaphthene Beijerinckia sp., Pseudomonas putida, Pseudomonas fluorescens, Pseudomonas cepacia

Bacterial strain degrading PAHs

Compound Organisms

Anthracene Beijerinckia sp., Mycobacterium sp., Pseudomonas putida, Pseudomonas fluorescens, Pseudomonas paucimobilis, Pseudomonas cepacia, Rhodococcus sp., Flavobacterium sp, Arthrobacter sp.

Phenanthrene Aeromonas sp., Alcaligenes denitrificans , Arthrobacter polychromogenes , Beijerinckia sp. , Mycobacterium sp. , Micrococcus sp., Vibrio sp., Pseudomonas putida, Pseudomonas paucimobilis, Rhodococcus sp., Nocardia sp., Flavobacterium sp., Streptomyces griseus, Acinetobacter sp.

Compound OrganismsFluoranthene Alcaligenes denitrificans , Mycobacterium sp. ,

Pseudomonas putida , Pseudomonas paucimobilis, Pseudomonas cepacia , Rhodococcus sp.

Pyrene Alcaligenes denitrificans , Mycobacterium sp. , Rhodococcus sp.

Chrysene Rhodococcus sp.

Benz [a] anthracene Alcaligenes denitrificans , Beijerinckia sp. , Pseudomonas putida

Benz [a] pyrene Beijerinckia sp., Mycobacterium sp.

POLYCHLORINATED BIPHENYLS (PCBS)

• Synthesized chemicals from petro-chemical industry used as lubricants and insulators in heavy industry

• Used because– Low reactivity– Non-flammable– High electrical resistance– Stable when exposed to heat and pressure

Fungal Degradation

• Aspergillus niger: fillamentous with cytochrome p450 that attacks lower chlorinated PCB’s

• Phanerochaete chrysosporium: White rot fungi can attack even highly chlorinated PCB’s at low conc. (less than 500ppb) while aerobic degradation is occuring at a level of 10ppm.

Some m.o. involved in the biodegradation of xenobiotics

ORGANIC POLLUTANTS ORGANISMS

Phenolic - Achromobacter, Alcaligenes,

compound Acinetobacter, Arthrobacter,

Azotobacter, Flavobacterium,

Pseudomonas putida

- Candida tropicalis

Trichosporon cutaneoum

- Aspergillus, Penicillium

Benzoate & related Arthrobacter, Bacillus spp., compound Micrococcus, P. putida

Organic Pollutants Organisms

Hydrocarbon E. coli, P. putida, P. Aeruginosa, Candida

Surfactants Alcaligenes, Achromobacter,

Bacillus, Flavobacterium,

Pseudomonas, Candida

Pesticides P. Aeruginosa DDT B. sphaericus Linurin

Arthrobacter, P. cepacia 2,4-D

P. cepacia 2,4,5-T Pseudomonas spp., E. coli, Parathion

P. aeruginosa

SUMMARY Xenobiotics are chemical compounds foreign to the body, such as drugs, food additives, and environmental pollutants Xenobiotics are metabolized in two phases. The major reaction of phase 1 is hydroxylation catalyzed by a variety of monooxygenases, also known as the cytochrome P450s. In phase 2, the hydroxylated species are conjugated with a variety of hydrophilic compounds such as glucuronic acid, sulfate, or glutathione. The combined operation of these two phases renders lipophilic compounds into water-soluble compounds that can be eliminated from the body. Xenobiotics can produce a variety of biologic effects, including pharmacologic responses, toxicity, immunologic reactions, and cancer.

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