Download Route of exposure, mode of action and modifying factors

Route of exposure, mode of action and
modifying factors
Important considerations – interaction of animals and
plants with xenobiotics
Exposure
Uptake
Transport
Storage
Metabolism
Excretion
LEAF
Uptake barriers are important.
For example:
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Exposure vs. uptake of toxicant from
air and rain in plants
EPIDERMIS
(stomata)
– Atmospheric concentration is important,
but what more important is what gets
into the plant
– Stomata might be completely
closed/regulated by CO2, temperature,
humidity light, water, nutrients
(potassium in particular)
– When the stomata are closed the
toxicant might not be able to get into the
plant
– Pollutants like ozone on the other hand
may affect the membrane material to
form toxic substance, such as
aldehydes, ketones and various free
radicals
INTRACELLULAR SPACE
SPONGY PARENCHYMA
PALISADE PARENCHYMA
EXCRETION
• In animals the exposure may be
– Dermal
• skin
• Water pollution e.g. swimming in a polluted lake
– Inhalation
• lungs
• air pollutants e.g. ozone, lead, methyl mercury
– Ingestion
• intestine
• pollutant in food; e.g. PCBs in fish we eat
• Immediate and long term effects are directly linked to the
mode of entry into the body
– The most common place of entry in animals is the skin through
follicles, sweat glands, and wounds
– Toxicant has to pass through a series of membranes (tissue, cell,
capillary
• Uptake / how to get through a membrane
– Passive diffusion
– Facilitated diffusion
– Active transport
• Lipophilicity (Kow) of a compound is important, because it affects
adsorption properties
• Transport
– Lymphatic system
– Blood system
– Transport is usually achieved through blood protein that binds the
toxicant – e.g. a lipoprotein
• Storage
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Liver
Lungs
Kidneys
Bone
Adipose (fat) tissue
Toxicant may be stored in one reservoir but later transported elsewhere
depending on physiological conditions
– Storage site may or may not be the site of the toxic effect
• Lead (Pb) is stored in bone, but it’s toxic effect is in the liver
• DDT is stored in adipose tissue but it’s effect is through prolonged gradual
release
Metabolism
• Toxicants are metabolized by
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Lungs
Gastrointestinal tract
Skin
Kidneys
Central role : liver
• The liver contains many non-specific enzymes that give it the ability
to metabolize a broad spectrum of organic molecules
• Two phases:
– Phase I involves the addition of reactive polar groups through oxidation,
reduction, or hydrolysis; sometimes this makes a non-toxic chemical
more toxic
– Phase II involves conjugation with an endogenous substance to form a
complex secondary metabolite which is more water soluble so it can be
excreted
• General mechanism of action of xenobiotics
– Intrinsic activity
– Activated metabolites
– Interact with specific site of action to initiate toxic effect
– Effect can be anywhere in the body
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Oxidative metabolism
Central nervous system
DNA replication (cancer and reproduction)
Protein synthesis
Protein function
– Effect can be
• Be terminated by
– storage
– transformation
– Excretion
• Permanent
Disruption or destruction of cellular structure
– Structural damage to tissue
• Plants
– SO2, O3, NO2 and fluoride are for example phytotoxic
– Feedback: SO2 weakens stomata which lets even more SO2 into cells
• Animals
– SO2, O3 can cause irritation and damage to the respiratory system
pulmonary edema
• fluid buildup in alveoli due to membrane disruption
– Industrial solvents can cause narcosis
• General symptomatic response to toxicants
• Results from membrane alterations / ion-transport
• logKow (log([octanol]/[water])) is used to asses hydrophobicity of toxicants
(correlates with toxicant’s ability to cross lipid membranes)
• Narcosis
– Alteration of physical/chemcial proterties of lipid bilayer
• Permeability
• Fluidity
– Interact with pumps and receptors
– Affect enzyme function
Binding to cellular constituents
• Xenobiotics my directly bind to a cellular component and inhibit it’s
normal function
– Carbon monoxide (CO) binds to hemoglobin (Hb) in red blood cells and
prevent the Hb from binding O2
– Cadmium; highly toxic heavy metal that binds to metallothionein. This
occurs primarily in the kidneys where Ca-metallothionein accumulates
and is highly toxic to tubular cells
Effect on Enzymes
• Enzymes are proteins that are involved in biochemical catalysis i.e.
they help transform chemical structures. The purpose of a catalyst is
to increase the rate of a reaction
– Optimal function of enzymes depends on co-factors
– There are organic and inorganic co-factors = coenzymes
• vitamin K
• Mg, Mn, Zn, Ca, Fe, Cu, K, and Na
A pollutant may inactivate the active site of an enzyme
– Pb binds to –SH groups in cystein residues of proteins forming
disulfide-lead bridges and poisoning the enzyme
Enzyme
SH + Pb
Enzyme
S-Pb-S
inactive
– Organophosphates inhibit acetylchlolinesterase
Enzyme
• Inactivation of cofactors
– Fluoride inactivates the enolase cofactor Mg
• Mg cofactor
• Fluoride complexes with Mg and phosphate to form FMgPO4
complex and prevents the enzyme from functioning by scavenging
it’s cofactor
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Replacement of co-factors
– Be competes with Mg and Mn
– Cd can replace Zn e.g. superoxide dismutase
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toxic synthesis
– --SH or --NH2 groups; hydrogens are replaced with CH2COOH in alkylhalide
toxicants
– e.g. sodium fluoroacetate
– Concerted to fluorocitrate, which irreversibly binds to aconitase poisoning the
enzyme
Secondary effects
– Presence of toxicant causes production of toxic substances
• Chemicals that trigger ore repress immune responses
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histidine -> histamine (in Mast cells through decarboxylation)
Released to trigger immune response
Histamine is a powerful vasodialator
Increases permeability of blood vessels
Reduce blood pressure and lead to anaphylactic shock
Most extreme is vascular collapse
Antihistamines inhibit the function of histamines by structure
• Carbon tetrachloride
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Leads to massive release of epinephrine from sympathetic nerve
Epinephrine is a powerful hormone involved in sugar metabolism
Inhibits glucagon secretion
=> inhibition of glucose uptake in muscles
Increases blood pressure
Liver damage
• Chelation
– Atom of metal is chemically bound / sequestered by ring shaped
molecules
– O, N, or S act as electron donor to the metal
– This forms chelate rings that are extremely stable
– E.g. the Fe in hemoglobin and the Mg chlorophyll are examples of
chelated metals
Chlorophyll a
• Receptor mediated toxicity
– Hormones are small inorganic or organic molecules
that are used by the body to signal physiological
states or illicit responses
• Responses are very precise and specific to individual tissues
• Exceedingly small quantities are needed to illicit response
– Steroid hormones
• lipid soluble;
• androgens = testosterone and andosterone
• estrogens = estradiol, estriol, estrone
– Toxicants can mimic the shape of hormones
• block the hormone binding site
• illicit the response in lieu of the presence of the hormone
• are called hormone/endocrine disruptors
• Factors influencing the activity of toxicants
– There are many pollutants in the environment
– Their toxicity is influenced by
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Partitioning, fate, and transport
physiochemical properties
mode of exposure
Time
Environmental factors
Interaction
Biological factors
Nutrition, starvation
Genetics
Proteins (Mixed Functional Oxidases)
Lipids
vitamins
Sex / effect on males vs. females
Disease
Behavior
Chemodynamics
Bio-availabiltiy
• 2,3,7,8-TCDD
– Not very toxic to invertebrate animals
– Highly toxic to vertebrates
– Ingredient in agent orange
– Two modes of toxicity:
• Planar molecule that fits into the active site of a receptor protein (Ah – aryl
hydrocarbon receptor)
• Sort of ‘velcros’ / stacks with aromatic structures in proteins
Ukrainian opposition leader Viktor
Yushchenko was poisoned by TCDD
• Activity of a toxicant depends on chemical conformation
– Conformation determines how much a chemical mimics a natural
ligand (show table of DDT LC50s)
Examples
• dioxins
– Irreversibly bind to DNA - mutagen
– Lipid soluble – bioaccumulates
– Can interact with receptors
• PCBs
– May act as an estrogen
– Coplanar 3,3’,4,4’,5,5’-hexachlorobiphenyl (HCB) resembles 2,3,7,8TCDD => is toxic by a similar mechanism