Toxicology
Terms
- Main purpose of Phase II rxns, and give reasons why they readily occur in the organism
-
May not be hydrophilic enough to be eliminated from the body
must undergo phase II rxn to form conjugated metabolite, which is easier for body to eliminate
occur readily because "conjugating agents" are readily available
-
What is glucoronide conjugation?
What's the conjugating agent?
What's the general name of the product of glucoronide reactions?
-
conjugation is the production of a conjugated metabolite using sulfate conjugates. Produces a high molecular weight polar conjugated metabolite that is readily excreted in urine.
low-capacity pathway because of small pool of sulfates in the cells
-
What is glutathione conjugation?
general structure of this conjugating agent
what's the importance of the -SH group?
-
- production of conjugated metabolite using glutathione as the conjugating agent.
- can react with a variety of xenobiotic substances; is a tri-peptide
- crucial to form covalent bond to the xenobiotic
-
What is acetylation?
what compounds readily undergo acetylation?
-
- reactions that are catalyzed by acetyltransferase enzymes, where an acetyl group is attached and acetyl CoA is involved
- aromatic amines easily undergo this
-
What is methylation?
What's the name of the conjugating agent?
-
- when methyl groups are attached to electron-rich O,N and S atoms
- conjugating agent is S-adenosylmethionine (SAM)
-
What is enzyme induction?
What is enzyme inhibition?
-
- prior exposure to environmental chemicals and drugs results in enhanced capability for biotransforming a xenobiotic
- slow down or stop enzymes from performing normally
-
What substances behave as inhibitors?
-
Metals (cadmium, mercury, lead)
Organic compounds
- What substances behave as inductors?
-
- alcohols
- PAH's (e.g. dioxin)
-
Define bioactivation and list species involved in the process
-
- process by which xenobiotic is converted to reactive or more toxic metabolite
- electrophilic species (+vely charged, or partially +ve charged - attracted to e- rich atoms: N,O,S)
- nucleophilic species (-vely charged or partially charged; -
Define LD50, LC50 and LT50
-
LD50 = dose of a toxicant expected to kill 50% of pop'n. When route of exposure is inhalation, can be expressed as:
- LC50 = lethal concentration (includes time of exposure)
- LT50 = lethal time (includes [] of chemical in air) - List the 3 kinds of toxicity studies
-
1) Acute
2) short-term
3) long-term - Explain the different components of an acute study. Indicate its goals
-
- determine median lethal dose (LD50); may also provide information on target organs, specific toxic events, guidance on dose to be used in short/long term studies
Components of study:
- selection of animal species
- route of administra -
What is a dose response curve?
-
plots cumulative mortality (%) vs. dose on a log scale, obtaining a sigmoid curve
curve between 16-84% is sufficiently straight for estimation of LD50
-
What are probit units?
how are they used in dose-response curves?
-
- equivalent to 1 std dev of normal distribution of deaths over time
- used to plot % mortality when determining LD50 of given toxicant; particularly useful when 2 or more toxicants have similar LD50's
-
Compare toxicity levels of different compounds by using dose response curves
-
- different LD50: flatter slope = more toxic substance
- same LD50: steeper slope = more toxic (smaller dose to detect response)
-
What is NOAEL?
-
- max dose[], or amount which causes no detectable adverse effect
determined from long-term studies, along with data on their acute toxicity and metabolism
-
What's a gene?
-
region of DNA controlling a hereditary characteristic
corresponds to a sequence used in prod'n of a specific protein or RNA sequence
carries biological information that must be copied/transmitted to progeny
-
What's the difference between genotype and phenotype?
-
- genotype = internally coded, inheritable information controlling synthesis of proteins and regulation of metabolism
- phenotype = outward physical manifestation of genes
-
How are polypeptides formed?
-
transcription: DNA template used to synthesize mRNA, which migrates to cytoplasm
translation: ribosome binds to mRNA, proceeds to add amino acids complimentary
-
Explain 2 types of gene mutations
-
1) base pair substitution: switch A:T with G:C. Gene encodes for no AA or wrong AA. May stop protein synthesis
2) frameshift mutation: DNA loses or gains 1 or 2 base pairs. Changes codon and fails to produce protein, or makes useless protein
- Explain the kinds of chromosome aberrations
-
1) breaking or re-arrangements: chromosomes break and/or rearrange incorrectly during replication
2) changes in # of chromosomes
a) one extra chromosome present = "aneuploidy"
b) exc - Define "mutagenesis"
-
phenomenon by which inheritable traits result from alterations of DNA
- What happens during oxidative alteration, adduct formation and intercalation?
-
- xenobiotics can affect fxnl groups in a DNA base (A,G,C,T) by attaching oxygen atoms to replace teh amino groups present in the ring, altering their structure (rearrangement occurs). This results in
- a different compound bein - List fxnl groups used to identify potential mutagens
-
- aromatic
- halogentated xenobiotics
- epoxides
- azo compounds (-N=N-)
- hydraxines (-N-N-)
- carbamates (N-COO-)
- organic amines -
Explain difference between somatic and germ cells
-
somatic = any cell forming body of an organism
germ = part of germline; involved in reproduction of organisms
-
explain the ames test
-
assay to assess mutagenic potential of chemical compounds. Based on inducing growth in genetically altered strains of Salmonella typhimurium (which require histidine to grow), on histidine-free medium.
- revertants able to grow on histidine
- explain how the results of a mutagenesis test are evaluated
-
- run 3 mutation tests (salmonella, mammalian gene, and mammalian cell-chromosomal)
- if all 3 are -ve --> presumed mammalian non-mutagen
- if any 2 of 3 are +ve --> mammalian mutagen
- if 1 is positive, conduct a Drosophila sex-l -
Define cancer
-
condition characterized by uncontrolled replication of the body's cells
occurs because genes that regulate cell division have been affected
can spread by:
- invasion (infect adjacent tissues)
&nb -
List carcinogenic agents
-
- biological (fungus, viruses)
- radiation (xray, gamma ray, cosmic ray -->produce ionized molecules and free radicals which are harmful to DNA)
- chemical (natural or synthetic substances) -
define chemical carcinogens
-
induction or enhancement of uncontrolled growth (tumor/neoplasia) in a tissue or organ caused by natural or synthetic chemicals
- Explain mode of action of chemical carcinogens
- Most are inactive to start with. Initiation --> bioactivation; pre-carcinogen can be eliminated, or yield reactive metabolites. Reactive metabolite can make covalent bond with GHS, etc to give conjugated chemicals that can be eliminated, or cause chang
-
Define genotoxic and epigenetic carcinogens
-
genotoxic --> initiate tumor by producing DNA damage.Includes ultimate carcinogens and pre-carcinogens, or electrophilic species binding to DNA
Epigenetic carcinogen --> don't damage DNA, but enhance effect of genotoxic carcinogen. Can
-
Define teratogenesis
-
formation ocongenital defects
-
Identify cell processes that can be affected by teratogens
-
RNA translation
metabolic processes
-
Mode of action of teratogens
-
Interfere with RNA translation --> production of enzymes involved in cell differentiation is inhibited or affected
Deprive metabolic processes of O2 and substrates
- Describe effects of teratogens
-
1. May cause malformations involving internal or external structure.
a. major (spinal bifida)
b. minor (abnormal pelvic development)
c. may or may not affect survival
2. May - Define endocrine disruptors
-
any exogenous substance that affects the natural role of hormones
-
Identify the main endocrine glands
-
pituitary, parathyroid, thyroid, thymus, adrenal, ovaries/testies
-
Describe the basic fxns of hormones
-
chemical messengers
control basic fxns such as growth, physiological, or behavioural responses
- male/female development (estrogens/androgens)
- growth (thyroxin)
- blo - Define homeostasis
-
- to maintain an internal balance vital for survival
- to regulate its internal environment
- Describe consequences of endocrine disrupters on human health
-
- bind to hormone receptors, blocking binding of hormone
- excess of hormones in bloodstream
- prevent synthesis of other hormones, responses- negative effects on reproduction and sexual deve
-
Describe the internal organization of a mitochondrion
-
made up of 2 membranes
- outer = permeable to small molecules and ions; no transporting proteins involved
- inner = highly corrugated and folded; resistant to penetration of any ions and most uncharged molec -
Explain how the TCA cycle and ETC are coupled
-
TCA cycle breaks down the C2 and C4 molecules further; C atoms are released to form CO2; e- and H+ are picked up by co-enzymes and reduced to NADH and FADH2 (end products of TCA)
H+ and e- combine with O2 to form water; e- flow through enzyme sys
- list 2 co-enzymes involved in the transfer of e- and H+
-
NAD+ and FAD (nicotinamide and flavin adenine dinucleotide)
-
explain the role of e- carriers, and give the names
-
sequence: flavoprotein --> FeS protein --> Q enzymes --> cytochrome B --> cyt C1 --> Cyt C --> Cyt A --> Cyt A3
roles: initiated by NADH arriving from interior of mitochondrion (carrying 2e- and 1H+); 2e- passed to flavoprote
-
Explain the importance of the H+ gradient for production of ATP
-
drives synthesis of ATP
-
Explain the 2 fxns that molecular oxygen accomplishes in the ETC
-
1. oxidizes NADH and FADH2, enabling them to participate again in the TCA cycle as NAD/FAD, and is final acceptor of e-
2. provides energy for conversion of ADP-->ATP, which keeps H+ gradient in mitochondrion
- explain how xenobiotics can affect ETC/ATP prod'n coupling
-
1. inhibitors of ETC:
- insecticides/pain killers affect FeS
- fungicide inhibit Q enzyme
- antibiotic inhibit Cyt C
- CN binds to ferric form of Cyt A3, pr