Toxicology

Paracelsus

Known as the father of toxicology, he discovered the principle that "the dose makes the poison" and considered disease as an entity in itself.

Risk Assessment

Calculated as the product of hazard and exposure, it involves considering individual differences such as age and route of exposure, as well as the species-dependent nature of toxicity.

Clinical Toxicology

Focuses on the connection between toxic substances and resulting illnesses in individuals.

Forensic Toxicology

Investigates the medical and legal aspects of toxicology to determine causes of death or exposure to toxins.

LD50

Lethal Dose 50, the amount of a substance required to cause death in 50% of subjects in experiments, varies among species and is crucial in studying systemic effects.

Xenobiotic

Chemical substances not naturally produced in an organism, including drugs and toxicants, which can enter the body through various exposure routes.

Toxicants

Substances causing adverse biological effects, which can be physical, biological, or chemical in nature.

Toxins

Toxicants produced by living organisms, often proteins, that can induce harmful effects.

Dose-Response Curve

Illustrates the relationship between the dose of a substance and the response it elicits, starting at a non-zero point due to factors like turnover rates.

Toxicokinetics

Involves the processes of absorption, distribution, metabolism, excretion, and storage of toxicants in the body.

Toxicodynamics

Concerned with the effects of toxicants on biological systems, including the dose and exposure levels that lead to toxic responses.

Lipinski Rule of 5

A set of criteria including molecular weight >500, log P

Reactive Oxygen Species (ROS)

Molecules like superoxide and hydroperoxyl involved in oxygen toxicity and oxidative stress.

Nitric Oxide (NO)

A radical formed from Arginine via nitric oxide synthase, easily passing through cell membranes.

Antioxidants

Substances like glutathione that quench ROS species, protecting against oxidative stress and damage.

Phase 1 Metabolism

The initial step in metabolizing toxicants, introducing polar reactive groups to molecules through redox or hydroxylation reactions.

Fatty Acid Hydroxylase

A type of P450 enzyme that catalyzes hydroxylation reactions on fatty acids, influencing their metabolism and properties.

Phase 1 Metabolism

Involves oxidation reactions like desulfuration and aromatic hydroxylation, leading to the formation of reactive intermediates.

P450 Enzymes

Enzymes responsible for drug metabolism, where inhibition or induction can lead to drug-drug interactions affecting the activity of various drugs.

Phase 2 Metabolism

Involves conjugation reactions that increase molecular weight and aid in the excretion of compounds, often dependent on the availability of substrates.

Glutathione (GSH)

A key molecule involved in detoxification, reacting with electrophiles to form covalent adducts and protect against toxicants.

Glucuronidation

A detoxification pathway where glucuronic acid is conjugated with xenobiotics, typically aiding in the excretion of compounds but not always leading to detoxification.

Polycyclic Aromatic Hydrocarbons (PAHs)

Compounds with two or more aromatic rings, where metabolism by P450 enzymes can lead to the formation of reactive intermediates with potential carcinogenic effects.

UDP-Glucuronosyltransferases (UDPGTs)

Enzymes associated with P450 that catalyze the conjugation of glucuronic acid with xenobiotics, aiding in detoxification in most cases but not always.

acute systemic toxicity

after exposure the affect is immediate

ADMET(S)

• Absorption of the toxicant

• distribution of the toxicant

• metabolism of the toxicant

• excretion of the toxicant

• Toxicology

• storage of the toxicant

ED50 (effective dose 50)

when 50% of people have a response to the xenobiotic

Mathieu Orfila

found that chemical agents such as arsenic can be used to kill people that can be found via post death report

synergism

toxic response is greater than additive effects

Potentiation

when one drug does not elicit a response on its own but enhances the response to another drug

coalitive

2 substances that might lead to a toxic response different from either of the two substances

antagonism

bind to endogenous receptors but don’t produce a response

TD50

produces a toxic response in 50% of subjects

therapeutic index

measure of TD50/ ED50 (toxic dose/ effective dose)

therapeutic index comparison

higher TI the lower chance toxic side affects occur;TI>10 is safe; while TI<2 is narrow therapeutic drug

margin of safety

TD1/ ED99 (TD in 1% of subjects/ ED in 99% of subjects) larger the better

Ficks law

rate of diffusion= k*A(C(inside)-C(outside))/ d

ROS has 2 classes:

radical and non-radical species

Drug -Drug interactions

can induce increase or decrease activity of P450

consequences of metabolism

• formation of chemically stable metabolites leading to detoxification, lack pharma logical/ toxicological activities or

• generation of short lived reactive metabolites leading to toxicological activation

• formation of chemically stable but pharmocolgically active metabolites

features of phase 2 metabolism

Conjugation increases MW, pKA slightly which lead easier excretion of compounds and is dependent on availability of other substrate

nomenclature system of PAH

1. find the highest priority group in the compound

2. number atoms

3. number edges (bonds between C on outer ring) with letters

James and Elizabeth miller

found that most carcinogens are mutagenic after they are metabolized and that mutagenicity depends on the extent of conversion to reactive electrophile