Palise Biochem Exam 3

Pharmacogenomics

The study of how a person's entire genome influences their response to medications, focusing on multiple genes and their interactions to understand variations in efficacy, safety, and metabolism.

Pharmacogenetics

A subset of pharmacogenomics that examines how variations in a single gene or a small set of genes affect an individual's response to a specific drug.

Personalized Medicine

An approach that tailors drug choice and dosage to an individual's genetic makeup for safe treatment.

Phase I Metabolism

A metabolic process that activates drugs through oxidation, reduction, or hydrolysis. Mostly activates drugs.

Phase II Metabolism

A metabolic process that typically inactivates drugs through conjugation. (acid addition).

How do CYP polymorphisms effect metabolization and distribution? What do UM and PM mean?

Effects metabolism but distribution is less likely.

UM: ultrarapid metabolism (GoF), drugs therapeutic effect is reduced, prodrug causes toxicity

PM: poor metabolizer (LoF), drug triggers toxicity at therapeutic doses, prodrug reduces therapeutic effect

CYP2C9 Substrates and effects.

Sub: Phenytoin and Warfarin

poor metabolizer (LoF) = risk of toxicity and bleeding

ultrarapid metabolizer = no effect

N-acetyltransferase type 2 (NAT2)

Subs: INH, Isoniazid, pyrazinamide, procainamide, caffeine

An enzyme where rapid acetylators have reduced toxicity.

Uridine diphosphate Glucuronosyl Transferase (UGT)

Acts on the prodrug Irinotecan, decrease in UGT1A1 phase 2 conjugation; slow metabolizers face higher toxicity to irinotecan chemotherapy

Thiopurine MethylTransferase (TPMT)

An enzyme requiring genetic testing for TPMT genotype before starting treatment for drugs like azathioprine.

Decreases in TPMT activity = toxicity to thiopurine chemotherapy

Pseudocholinesterase

An enzyme affecting Succinylcholine; high activity can lead to respiratory paralysis and malignant hyperthermia.

Low enzymatic activity = respiratory paralysis***

VKORC1 Polymorphism

= Lower protein expression and increased warfarin sensitivity

manage by lowering drug dose

B2-adrenergic Receptor

AA variant that downregulates gene = effect of drug reduced

manage by increasing dose

is resistance to down regulation = high effect of agonist drug = overstimulate B2 receptor = toxicity

Toxicant

Any toxic chemical or agent that can cause harm.

Poison

A substance that kills, injures, or impairs an organism through its chemical action.

Xenobiotic Agent

Any substance foreign to the body.

Hazard

The innate toxic effect of a chemical, posing risks at high exposure levels.

Threshold

The dose below which no effect occurs.

Toxic Effect

Abnormal effects causing anatomical or functional damage.

Carcinogen

A substance that can cause cancer.

Mutagen

A substance that can cause genetic mutations.

Teratogen

A substance that can cause physical defects in a developing embryo.

Clinical Toxicology

The study of toxic effects of drugs in living organisms, methods of detection, diagnosis, and their treatment.

Developmental Toxicology

The study of adverse effects of toxicants on developing organisms during lifespan.

Environmental Toxicology

The study of adverse effects of environmental pollutants on ecosystems.

Forensic Toxicology

The study of medical evidence of poisoning in human deaths.

Mechanistic Toxicology

Understanding the cellular, biochemical and molecular basis of toxic effects.

Regulatory Toxicology

Developing regulations to control exposure to dangerous chemicals.

Economic Toxicology

Related to food and drug toxicology.

Industrial Toxicology

The study of chemical substances emitted by industries and ambient air and water.

Genetic Toxicology

The study of the effects of xenobiotics on genetic material.

Describe sources/Exposures and types of poisoning

Dose

The amount of a substance administered or absorbed by an organism.

Dose-Response Curves

relationship between dose and effect magnitude.

Establish chemical effects, determine threshold effects, and the rate at which the effect occurs

Estimate risk, Determine safe exposure levels, Understand the potential for harm.

Acute Poisoning Treatment

Initial steps include obtaining information, inducing emesis, and using adsorbents like charcoal, transport to ER. →

At ER: initial exam, remove unabsorbed toxicant using emesis unless it contradicts, administer antidotes, give supportive treatment, speed up elimination of toxicant

Factors in Toxicant Damage to cells /tissues

Dose, nature of exposure, tissue/cell characteristics, rate of initial insult, and progression factors like inflammation.

Mechanisms of Toxicity

Include receptor-ligand interactions (PCBs and dioxin)

Oxidative stress

Interference with energy production, covalent bonding, lipids' peroxidation, disrupted calcium homeostasis, selective cell death, cell death signaling, and dysregulation of gene expression.

Drug Toxicity

Can result from prescription medications, over-the-counter drugs, and illicit drugs.

Therapeutic effects or toxic effects

Metal Toxicity

Environmental or occupational exposure, contaminated food/products

Varies by metal; can cause neurotoxicity, nephrotoxicity, hepatotoxicity, carcinogenesis, and teratogenesis.

Dioxin Toxicity

Industrial byproducts, natural sources (volcanoes, forest fires)

Highly toxic, persistent environmental pollutants

Causes teratogenesis, cancer, immunosuppression, liver damage, chloracne, and endocrine disruption.

Natural Chemical Toxicity

Certain mushrooms (ex. amanita phalloides -death cap)

Cyclic peptide hepatotoxins = hepatorenal syndrome, death

Pollutant Toxicity

Tobacco smoke: COPD, lung cancer, asthma, heart disease, reproductive problems

Carbon monoxide

Particulate matter- heart disease, stroke, asthma, COPD, lung cancer, diabetes, obesity, cognitive impairment, neurodegenerative diseases