Liver detoxification Flashcards
What are the types of compounds?
1) Exogenous (Foreign substances “xenobiotics”)
- Herbicides
- Pesticides
- Air pollutants
- Alcohol
- Pharmaceuticals
2) Endogenous (internally created substance)
- Gut toxins
- Hormones
- Bile acids
- Urea
- Bilirubin
What is the role of the liver in detoxification?
- Major role in carbohydrate, fat, and protein metabolism also:
1) Secretion of bile
2) Detoxification
3) Metabolism of vitamin A, D, K, E
4) Production of clotting factors (especially prothrombin)
What are the organs that have some detoxification properties?
1) Lung
2) Kidney
3) Skin
4) Intestine
What is the main mechanism of liver detoxification?
The overall aim is to increase the solubility of toxic substances enhancing their secretion from the body (via urine, bile, and feces), they achieve this by adding polar functional groups/conjugates
What are the steps in liver detoxification?
1) Phase I: Functionalization, oxidized by adding a functional group (ex, hydroxyl, carboxylic, thiol, amine)
2) Phase II: Conjugation (converting the metabolites to polar, soluble, and extractable metabolites by adding conjugates like,
1) Glaucouronic acid, 2) glycine, 3) glutamine, 4) glutathione, 4) Sulfate, 5) Acetate,
6) thiosulfate, 7) taurine)
What is the main reaction in phase I?
“Hydroxylation” -OH addition, catalyzed by mono-Oxygenases (incorporate one atom from molecular oxygen into a substrate) or Cytochrome P450s mixed function oxidases
- Generally, substances are converted from lipophilic to hydrophilic
R-H + O2 + NADPH (imp for the neutralization of free radicals) + H+ → R-OH + H2O + NADP+
Description of Cytochrome P450
- Large class of heme proteins with absorbance at 450nm that are located in the liver inside the endoplasmic reticulum and mitochondria
- It has 400 isozymes and 36 families
What is the difference between the monooxygenase system and the microsomal system?
the microsomal system encompasses a cellular fraction containing microsomes, and it includes a variety of enzymes, with cytochrome P450 monooxygenases being a significant component. On the other hand, the monooxygenase system specifically refers to enzymes that catalyze monooxygenation reactions, and cytochrome P450 enzymes are examples of such monooxygenases found in the microsomal system
What is the importance of the microsomal system?
- Associated with the membrane of the smooth endoplasmic reticulum, and has an importance in the detoxification of foreign compounds (xenobiotics)
The purpose of these modifications:
1) activate or inactivate a drug
2) make a toxic compound more soluble
3) Frequently, the new hydroxyl group will serve as a site for conjugation with a polar molecule, such as glucuronic acid
Imp function of the cytochrome P450 monooxygenase system found associated with the inner mitochondrial membrane is the biosynthesis of steroid hormones (Vitamin D3)
What are the inducers of phase 1?
1) High intake of alcohol
2) Increased tobacco smoking
3) Increased medications
Chiefly explain Phase II
When a toxic compound being foreign or endogenous combines with a polar compound in the body making the toxic substance more water soluble to be easily excreted
The most common conjugate is glucuronic acid (from UDP-Glucuronic acid), the enzyme responsible for the transfer of glucuronic acid is UDP-glucuronyl transferase found in the endoplasmic reticulum of hepatocytes and it is inducible by drugs like barbiturates
(It removes a hydrogen from the metabolite and adds a gluconate)
- Example is the addition of glucuronic acid to bilirubin making it water soluble
How is alcohol detoxified?
- The basic enzymes are Alcohol dehydrogenase (ADH) “converts alcohol to aldehyde” & aldehyde dehydrogenase (ALDH) “converts aldehyde to an acid”
In the metabolism of methanol (alcohol), what can cause blindness?
The end product Formic Acid
What is the secondary pathway of alcohol metabolism?
- Microsomal Ethanol Oxidizing System (requires oxygen)
The primary enzyme involved is CYP2E1, induced in chronic alcoholism
- The byproducts of this metabolic pathway, especially ROS and acetaldehyde, can contribute to liver damage and other health issues.
What does the cytochrome P450 contain?
Iron and Heme
