Foundations Exam 3 Material - Toxidromes, Nucleotide Metabolism, DNA Replication, DNA Repair

Define toxicology

study of deleterious effects of chemicals and physical agents on living systems

Define toxic or toxicity

ability of an agent to cause injury, potential to inflict an adverse or deleterious effect

Define toxicant/poison

harmful substance produced by man-made activities or organisms

All substances have the potentials to be_______

poisons

Define toxin

any harmful substance produced naturally by organisms (synthesized by plants or animals)

Define xenobiotic

substance that is foreign to the body or to an ecological system

What is a type A classification of Adverse Drug effect?

either non-deleterious or deleterious un-desireable side effects

What is type B classification of adverse drug effect?

idiosyncratic effects

What is a non-deleterious ADR?

side effect

What is a deleterious ADR?

toxic effects

What is an idiosyncratic effect?

unusual, unexpected response to a drug that may manifest itself by overresponse, underresponse, or response different from the expected outcome

Define side effects

unwanted or harmful effects that occur at therapeutic doses of a drug; usually minor (NVD< dizziness, HA), decrease or disappear upon decreasing dose or sometimes with continued use of drug

Define toxic effects

serious, required stoppage of drug use, often require supportive treatment to save life, long-lasting pathological damage possible, may affect the genome

Describe target adverse effect

exaggeration of the desired pharmacologic action due to too much dug presented to the receptors

What is an example of on target adverse effect?

atenolol normally decreases heart rate, excessive amounts will stop hearts from beating

Describe off-target adverse effect

activating unintended receptors in the body

What is an example of an off-target adverse effect?

SSRI citalopram can activate muscarinic-1 receptors to cause confusion

describe idiosyncratic effect or reaction

abnormal reactivity to a drug that is specific to a given individual (allergic reaction), non-dose related, extreme sensitivity to low doses common

Idiosyncratic effects are often due to a

pharmaco-genetic polymorphism in specific enzymes

What groups are more susceptible to adverse drug effects?

elderly (reduced clearance), patients on many drugs (poly-pharmacy), patients with pre-existing diseases (GI disease decreases absorption), genetic enzyme variations, fetus during pregnancy, young child fed through lactation

What are the 5 FDA pregnancy categories?

A,B,C,D,X

Describe category A

failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters)

Describe category B

failed to demonstrate a risk to the fetus and there is no adequate and well-controlled studies in pregnant women

Describe category C

There are potential benefits that may warrant use of the drug in pregnant women, despite potential risks; animal studies show adverse effects but not adequate and well-controlled studies in humans

Describe category D

positive evidence of human fetal risk, but potential benefits may warrant use

Describe category X

fetal abnormalities and/or there is a positive evidence of human fetal risk

What is an FDA black boxed warning?

found in package inserts, FDA's strongest warning to the public, significant risk of serious and even life-threatening adverse drug reactions; dispensing medications pharmacist has to read boxed warning

Describe box warning

FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use if restricted

Describe REMS

Risk evaluation and mitigation strategy; methods from manufacturers to ensure that the benefits of a drug or biological product outweighs its risks

REMS educational responsibilities are placed on _________ to instruct physicians prescribing and patients taking REMS drugs on potential risks, patients instructions reinforced

pharmacists

What do variations in an individual's response to a toxicant can depend on?

gender, genetics, age, health conditions (liver, kidney excretions, GI elimination)

Overtime the amount of chemicals in the body can build up and redistribute and ________ repair mechanisms

overwhelm

What is acute toxic exposure?

immediate in less than 24 hours, usually single exposure

What is a subacute toxic exposure?

within 1 month, repeated doses

What is sub-chronic toxic exposure?

1-3 months, repeated doses

What is chronic/delayed toxic exposure?

more than 3 months, repeated doses

What is an informational pathway?

pathway in which genetic information is stored as the nucleotide sequence is maintained and expressed

How is information from parenteral DNA copied to daughter DNA with high fidelity?

DNA replication

How is RNA synthesized using DNA as a template?

transcription

How are viruses able to make RNA and DNA using RNA as a template?

Reverse transcription

Define gene

segments of DNA that code for peptides and RNA; different from regulatory sequences, DNA can be expressed differently to yield different products

How is DNA involved in transcription?

one strand of double-stranded DNA acts as the molecular template for RNA synthesis

What happens in translation?

triplets of nucleotides in mRNA bind complementary triplets in tRNA

What determines biological function?

the protein sequence

Human somatic cells have how many chromosomes?

46 (22 diploid pairs plus X and Y)

Do mitochondria and chloroplasts have DNA?

Yes; double stranded circles

What is the majority of eukaryotic DNA?

non-coding DNA

(T/F) The total length of DNA, nor the number of chromosomes correlates strongly with the complexity of an organism.

False

How is eukaryotic DNA organized?

into a complex called chromatin

How much of the total genome encodes for proteins?

a small fraction (1.5%)

What are some non-protein things that are encoded in the total genome?

things that are involved in regulation of gene expression (promoted, terminations signals, etc), small regulatory RNA, junk DNA (pieces of unwanted genes, remnants of viral infections)

What are exons?

expressed sequences that are translated into the amino acid sequence

What are introns

regions of genes that are transcribed but not translated; do not encode polypeptide sequence

What happens to introns?

they are removed after transcription and the exon mRNA sequences are spliced together; creates mature transcripts

What are transposons?

sequences that can move around within the genome of a single cell

Describe transposon characteristics

ends of transposons contain terminal repeats, these repeats hybridize with complementary regions of target DNA during insertion; account for 50% of human genome

Describe simple sequence repeats (SSRs)

short sequences with millions of repeats also known as satellite DNA, associated with centromeres and telomeres

What are telomere sequences for?

may form special loop structures to keep DNA ends from unraveling

What adds telomere sequences to chromosomes?

telomerase

Describe cellular DNA aging

in many tissues, telomeres are shortened after each round of replication

What is the hayflick limit?

normal human cells divide about 52 times before losing the ability to divide again

What are centromere sequences?

AT-rich repeated sequences essential for equal distribution of chromosome sets to daughter cells; region where two daughter chromosomes are held together during mitosis

What is DNA supercoiling?

the formation of additional coils in DNA due to twisting forces

Why does DNA need to be organized?

packing of large DNA molecules within cells; access of proteins to read the information in DNA sequences

What is non-supercoiled DNA called?

relaxed

Supercoiling has great influence on ________ and ________ of DNA

transcription and replication

Is supercoiling regulated?

Yes

Most cellular DNA is under-wound in what form?

normal B-form

(T/F) Closed circular DNA is rarely relaxed

True

How is linear DNA underwound?

With the help of proteins to prevent strands from rotating

What additional DNA structural changes are facilitated by underwinding?

maintain structure of cruciforms at palindromes (cruciforms rarely occur in relaxed DNA), facilitate formation of stretches of left-handed Z-form

What are topoisomers?

Different forms of DNA that differ only in the degree and nature of supercoiling

What is required for conversion between topoisomers?

a DNA strand break

What type of supercoiled DNA travels faster in agarose gel electrophoresis experiment than relaxed or nicked DNA?

negatively supercoiled DNA

What do topoisomerases do?

cur DNA strands for DNA unwinding and rewinding during transcription and replication

What are the major types of topoisomerases?

type 1 and type 2

Describe Type 1 topoisomerase

makes a transient cut in one DNA strand

Describe type 2 topoisomerase

makes a transient cut in 2 DNA strands;

What is the type 1 topoisomerase mechanism?

Tyrosine reside attacks phosphate and cuts one strand; forms new bond to DNA strand, enzyme changes to an open conformation, unbroken DNA strand passes through the break in the first strand, enzyme in closed conformation, liberated OH attacks the linkage to re-ligate the cleaved DNA strand

What are the main eukaryotic topoisomerases?

Topo 1, 2alpha, 2beta, 3

What eukaryotic topoisomerases are type 1

Topo 1 and Topo 3

What are the two subfamilies of type 2 topoisomerases?

2a and 2b; can relax both positive and negative supercoils

What is the mechanism of eukaryotic type 2a topoisomerase?

Two tyrosines attack double stranded DNA, Second segment of the same DNA molecule (double stranded) passes through break, breaks are re-ligated via two ATP molecules

What are coumarins (novobiocin, coumermycin A1)?

drug that inhibits bacterial type 2 topoisomerases from binding ATP

What are quinolones(nalidixic acid, ciprofloxacin)?

inhibit the last step of topoisomerase, which is resealing the DNA strand breaks, wide-spectrum and mostly selective for bacterial enzymes (antibiotics)

How are topoisomerases used as chemotherapy agents?

target cancer because most rapidly growing cells (tumors, others) express topoisomerases

How do eukaryotic type 1 topoisomerase inhibitors work?

trap the enzyme-DNA complex in its cleaved state

What is chromatin?

fibers of DNA and protein where DNA associates tightly with proteins called histones

What are histones?

small proteins with lots of basic (Lys, Arg) residues (often positively charged)

What are nucleosomes?

DNA and protein packed into discrete units

What does wrapping of DNA around the histone core require?

the removal of one helical turn

When under-winding occurs without a strand break, what forms?

a compensatory positive supercoil

How is the positive supercoil relaxed?

By a topoisomerase, leaving DNA with a net negative supercoil

Where does histone binding occur more often?

AT rich regions, staggering at 10bp intervals that facilitate its binding around the histone core

What are some roles of nucleic acids?

cellular energetics, messengers (within the cell/mRNA from nucleus) and from outside the cell (in response to hormones), molecular repositories of information

How are nucleic acids involved in biotechnological processes?

genetic testing, vaccine development, drug development, nutraceuticals, metabolic engineering, etc

Nucleic acids have what properties?

ordinal and informative

What is a nucleotide?

nitrogenous base, pentose, and phosphate

What is a nucleoside?

nitrogenous base and pentose

What is a nucleobase?

only nitrogenous abse