EXAM TWO TOXICITY MATERIAL

most observable cellular changes and cell death are due to

underlying biochemical changes within the cell or in the surrounding tissue

T/F morphological changes follow functional changes

T

metabolisms of xenobiotics can lead to

toxic or nontoxic metabolites

selective toxicity depends on the _____ of the xenobiotic in the body and the ______ to the target tissue

distribution

absorption

the availability of ____ ___ depends on the species and the organ systen

metabolizing enzymes

T/F all xenobiotics must be metabolized to an active form to produce toxicity

F

an example of metabolic activation is a mycotoxin produced by aspergillus trains and is common contaminant in pet food

aflatoxin-B1

Aflatoxin-B1 is metabolized to reactive forms by

cytochrome P450

the most active metabolite of Aflatoxin-B1 is the _______ which forms covalent bonds with proteins and DNA

8,9-epoxide

the first stage of drug metabolism, mainly carried out in the liver by enzymes (especially the cytochrome P450 system). The goal is to introduce or expose a functional group on the drug molecule, making it more polar and ready for further modification in Phase II metabolism.

phase 1 metabolism

is the second stage of drug metabolism. Here, the drug (or its Phase I metabolite) is coupled with an endogenous, highly polar molecule. This makes the compound much more water-soluble and therefore easier to excrete in urine or bile.

phase 2

this is involved in phase two metabolism and Makes the compound water-soluble, non-toxic, and ready for excretion in urine or bile.

glutathione (GSH)

individual _____ factors can influence toxic response

susceptibility

_____ can cause inflammation

lipopolysaccharides (LPS)

a leftward shift in the dose response relationship indicates

more toxic to individuals

if Alflatoxin B has a leftward shift in the dose response relationship it indicates that

aflatoxin B is more toxic to individuals with inflammation

T/F individual factors can make more susceptible to toxicity

T

what are some factors that may influence Aflatoxin toxicity

age

gender

A/D

metabolism

elimination

co-existing disease

inflammation

nutritional status

a molecule or atom that contains one or more unpaired electrons

free radical

T/F a free radical may be charged or uncharged

T

includes oxygen free radicals and other nonradical but reactive oxygen species

reactive oxygen species

a disturbance in the pro-oxidant- antioxidant balance in favor of pro-oxidant

oxidative stress

oxidative stress is a shift towards a more _____ state in thr biomolecular pool

oxidized

T/F oxidative stress can be but is not necessarily damaging

T

How are ROS formed

by one electron reductions of oxygen

redox reactions involve the transfer of

electrons from one compound to another

in redox reactions one copmound is _____ and one is ______

oxidized (looses electrons)

Reduced (gains electrons)

the element or compound that gains electrons is said to undergo

reduction

free radical=

unpaired electron in outer orbit

Inside cells, oxygen (O₂) can accept an electron → forming

superoxide anion (O₂•⁻).

superoxide can go to ______ by an additional electron plus protons

hydrogen peroxide

Hydrogen peroxide reacts with ferrous iron (Fe²⁺) → producing the dangerous

hydroxyl radical (•OH)

ROS are very reactive especially the

hydroxyl radical

most ROS are generated as by products during ______

mitochondrial electron transport

T/F ROS production doesn't necessarily cause cell damage and toxicity

T

T/F generally toxicity occurs very close to the site of ROS production

T

cellular targets of ROS

Proteins

DNA

LIpids

lipid peroxidation results from

a free radical chain reaction in membranes

lipid peroxidation is

oxidative degradation of polyunsaturated fatty acids (PUFAs) in cell membranes.

with lipid peroxidation A ________ abstracts a hydrogen atom from a fatty acid side chain

hydroxyl radical (•OH)

when A hydroxyl radical (•OH) abstracts a hydrogen atom from a fatty acid side chain a ______ if formed

carbon centered radical

the carbon centered radical reacts with oxygen to form a

peroxy radical

lipid peroxidation is toxicant induced

hydrogen extraction

lipid peroxidation may result in

severe membrane injury

what three enzymes can help eliminate ROS

SOD=superoxide dismutase

Gs Px= glutathione peroxidase

GS Red= gluthione reductase

what does SOD do

converts superoxide to hydrogen peroxide

what does glutathione peroxidase do

detoxifies H2O2 using glutathione and makes H2O and Oxidized glutathione

Oxidized glutathione (GSSG) can later be recycled back to GSH by _______ using NADPH

glutathione reductase

which enzyme that helps eliminate ROS is selenium dependent

GS Px= glutathione peroxidase

what are some non enzymatic ROS scavengers

vit E

vit C

metal chelators

beta carotene

melatonin

antoxoidants are

electron donors

what do antioxidants do

hey donate one or more electrons to the free radical.

which conditions might be protective against oxidative stress

-vit e or c deficiency

- selenium deficiency

- GSH depletion

- genetic abnormality in which SOD is overactive

- genetic abnormality in which SOD is overactive

white muscle disease is a nutritional myopathy caused by

selenium or vit E deficiency

what is the underlying pathology of white muscle disease

free radical mediated rhabdomyolysis

who is susceptible to white muscle disease

young with fast growing muscle

_______ formation in RBC decreased glutathione and causes ROS

disulfide

plants that contain disulfide or disulfide like compounds

onions, garlic, leeks, cruciferous vegetables

______ activates photo toxin which causes free radicals then cell damage

UV radiation

what is the secondary and most common mechanism of plants causing phototoxicity

compromised liver function causes accumulation of phototoxin

xenobiotics can form _____ with proteins

covalent bonds

whats a covalent bond

an atom of the ligand contributes a shared electron or an unshared pair of electrons to the bond

______, _____, and ______ bind to xenobiotics through covalent bonds as they have lone pairs of electrons

sulfur, oxygen, and nitrogen

covalent bond formation with proteins is the primary mechanism of action in _____ toxicity

metal

type of covalent bond in which both electrons in the shared pair come from the same atom.

coordinate covalent bond

metals can cause

oxidative stress

metals bind ______ and deplete glutathione and promote oxidative stress

sulfhydryl groups

we can use the bonding properties of metals for _____ in the clinic

detoxification

_____ can bind to -SH groups on proteins

lead

lead binding to -SH groups can inhibit key enzymes in ___ synthesis and impairs the hemoprotein cytochrome P-450

heme

what systems are most affected with lead toxicity

GI

CNS

hematopoietic

Lead can replace _____ or _____ in metal dependent proteins

Ca or Zn

disrupted heme synthesis due to lead can cause

anemia

is activated charcoal effective in treating metal toxicosis

No

metals are eliminated by the _____ and can be nephrotoxic

kidneys

administration of ______ is the antidotal treatment for most metal intoxications

chelators

what is a chelator

any ligand that binds a metal ion with two or more atoms

what are two objectives of chelation therapy

enhance excretion of the metal

decrease interactions of the metal with biomolecules

T/F chelation therapy is almost always more effective when administered soon after exposure

T

chelation therapy PREVENTS interactions rather than ____ metal effects

reverses

number of atoms of a ligand that bind to a single metal ion

denticity

stability of a metal-ligan complex depends on

denticity

denticity 1=

monodentate ligands

denticity 2 =

bidentate ligands

denticity 4=

polydentate ligands

denticity 6=

hexadentate ligand

example of a hexadentate ligand

EDTA

T/F ligands of high denticity tend to bind metal ions more strongly than ligands of lower denticity

T

stronger bonds=

greater stability

why is denticity important

because many metals exchange ligands very rapidly

complexes with ____ ligands are more stable than comparable complexes of monodentate ligands

chelate

many metals have preferred

coordination environments

some ligands enforce a specific

geometry

some chelating ligands have a defined ____ size that is ideal for a certain size ion

pore

T/F not all chelators work on all metals

T

The dose of a chemical determines if

toxicity occurs