lecture 5- basic mechanisms of toxicants 3

oxidative stress

imbalance of cellular oxidants and antioxidants (in favor of oxidants)

direct generation of ROS/ RNS

a. Xenobiotic bioactivation* (i.e. carbon tetrachloride, benzene)

b. Redox cycling (paraquat, MPP+)

c. Transition metals (Fe2+, Cu2+)

d. Inhibition of mitochondrial electron transport (many phytochemicals)

xenobiotic bioactivation

A metabolic process where the body converts a foreign

chemical (xenobiotic) from a less reactive state into a biochemically active, toxic

intermediate. This often generates electrophilic compounds that damage cells.

indirect generation of ROS/ RNS

increased Ca can cause ROS/ RNS

induction of cytochrome P450

increased Ca can cause ROS/ RNS through 3 steps

i. Activates dehydrogenases in citric acid cycle and increases electron output (NADH and FADH2), leads to an increase in O2- (superoxide) by the e- transport chain.

ii. Ca2+ -activated proteases convert xanthine dehydrogenase to xanthine oxidase, the by- products of which are O2- . and H2O2.

iii. Neurons and endothelial cells constitutively express NOS that is activated by Ca2+ increase NO production which reacts with O2- to produce highly reactive ONOO- (peroxynitrite).

consiquences of ROS/ RNS

directly oxidize and affect protein function

oxidatively inactivate Ca/ ATPase

drain ATP reserves

compromises ATP synthesis

lipid peroxidation, cell swelling, and cell rupture

lipid peroxidation

1. free radicals initiate peroxidative degradation of lipids by hydrogen abstraction from fatty acids

2. lipid. radical formed is converted to the lipid peroxyl radical by oxygen fixation

3. lipid hydroperoxide is then formed by hydrogen abstraction from another lipid

ATP synthesis triangle corners

mutagens

cause changes to cell DNA that are heritable

if mutagens produces a neoplastic cell the agent is

carcinogen

mutagens are a subset of

genotoxic carcinogens

2 major classes of mutations

proto-oncogenes

tumor- suppressor genes

proto-oncogenes

promote cell cycle progression

example: mutations that increase activity of growth factor tyrosine- kinase receptors

tumor suppressor genes

inhibit cell cycle progression

example: mutations in tumor suppression gene product

teratogenesis

the creation of birth defects during fetal development

teratogens

substances that induce birth defects

blastocyte formation effect on fetal development

organogenesis effect on fetal development

maturation effect on fetal development

as above is:

division

migration

differentitiation

death

what causes this

a teratogenic plant called lupines

issue is called arthrogryposis or twisted legs

what are the six poisonous species that cause crooked calf disease

silky lupine

tailcup lupine

velvet lupine

silvery lupine

lunara lupine

yellow lupine

conium maculatum

(hemlock or poison hemlock) is a highly

poisonous biennial herbaceous flowering plant in the carrot

family Apiaceae

tree tobacco

nicotiana glauca a wild tobacco that affects cattle, sheep and goats

nicotiana tabacum

cultivated tobacco annually grown herbaceous plant

corn lilly or false hellesbore

veratrum californicum

cyclopamine

due to ingestion of corn lilly

inhibits the action of the hedgehog signaling pathway involved in formation of the neural system

now investigated as a potential anti cancer therapy

sedative

teratogen

manifestations of structural neurotoxicity

neuronopathies

axonopathies

myelinopathies

manifestations of functional neurotoxicity

neurotransmission- associated abnormalities

manifestations of structural neurotoxicity neuronopathies

• Injury or death to neurons, targets cell bodies

• Irreversible loss

• Initial injury followed by apoptosis or necrosis

manifestations of structural neurotoxicity axonopathies

• Primary site of toxicity is axon

• Degeneration of axon, also known as Wallerian degeneration

• Loss of axon distal to lesion

• Loss of surrounding myelin, and cell body remains intact

• Chromatolysis and margination of Nissl substance

• Irreversible in CNS, but reversible in PNS is possible

manifestations of structural neurotoxicity myelinopathies

• Intramyelinic edema

• Demyelination by affecting myelin or myelin-producing cells

• Remyelination in CNS occurs to a limited extent - oligodendrocytes

• Remyelination in PNS done by Schwann cells

manifestations of functional neurotoxicity neurotransmission- associated abnormalities

• Interruption of impulse transmission

• Blockade of trans-synaptic communication

• Inhibition of neurotransmitter uptake

• Inhibition of neurotransmitter removal / breakdown

• Interference with second-messenger systems

review