Toxicology Exan 2

What is the biological basis for the transformation of chemicals?

to convert lipid-soluble, non-polar, non-excretable forms of chemicals to water-soluble, polar forms that are excretable in bile and urine.

Why is the transformation process important to understanding human health?

It moves the focus from isolated treatments to sustained, whole-person preventative care.

How does cytochrome P 450 participate in the biotransformation process?

It can metabolize many xenobiotics

It can catalyze many types of reactions

It is widely distributed amonf tissues, and tissue distribution can vary.

It exists in multiple forms

Levels can be increased by exposure to chemicals found in food, water, or air.

What are the four primary enzymes involved in Phase II metabolism? Do these complement the actions of P 450?

1. Glucuronosyltransferase

2. Sulfotransferase

3. Glutathione-S-transferase

4. Acetyltransferase

5. Yes, they complement each other. While P 450 sometimes only adds a small degree of polarity, Phase II conjugation dramatically increases water solubility, deactivates pharmacological activity, and prepares the molecule for elimination via the kidneys or bile.

What factors affect biotransformation, and how do they affect our understanding of the biotransformation process?

1. Species, strain, and genetic variations

   1. Risk assessment is based on responses in animals, so there are often significant differences between species and their ability to matabolize xenobiotics

2. Age

3. Diet

4. Exposure to other chemicals

Define toxicokinetics in detail.

The study of the modeling and mathematical description of the time course of disposition (ADME) of xenobiotics in the whole organism.

Compare and contrast the one-compartment model and the two-compartment model used to evaluate toxicokinetics.

Similarities:

1. Both models simulate the ADME of xenobiotics to predict plasma or tissue concentration over time

2. Both diagrams use first-order elimination rate constants

3. Toxicant clearance or elimination ultimately occurs from the primary/central vascular space

Differences:

1. The one-compartment model simplifies the body into a single fluid volume for ease of calculation. the two-compartment model is more anatomically realistic becyase different body tissues naturally recieve varying tates of blood flow.

2. In the one-compartment model, tissue-to-plasma equilibirum is reached immediately upon administration. In the two-compartment model, a distinct, measurable periof of time is required for the toxicant to balance between the central blood supply and peripheral tissues.

Epigenetics

Epigenetic carcinogens induce cancer by altering gene expression.

Genotoxic carcinogens induce cancer by directly altering the DNA sequence.

Epigenetic mechanisms result in a threshold dose-response relationship because the cells in your body have a natural defense program, like homeostasis, that can compensate for minor epigenetic alterations, so a high dose of the chemical is needed to overwhelm these defenses and cause major harm.

A non-linear uncertainty factors model is used for epigenetics because of the threshold dose-response relationship.