Xenobiotics

Xenos in latin means STRANGER. Xenobiotic compound that is foreign to the body Biological basis for xenobiotic metabolism: To convert lipid-soluble, non-polar, non-excretable forms of chemicals to water soluble, polar forms that are excretable in bile and urine

Biotransformation reactions Phase 1: Enzymatic reactions that add or expose functional groups to xenobiotics such a OH, - SH, NH2 or COOH. A hitch is added. The xenobiotic is still lipophilic, poorly water soluble, possibly reactive, poorly excretable and has now been catalyzed by P450s

Biotransformation reactions Phase 2: Enzymatic reactions that result in the conjugation of large water-soluble, charged biomolecules to xenobiotics. For these reactions to occur a functional group must be present either on the parent molecule or its phase 1 product. The foreign chemical (xenobiotic) is now not lipophilic, usually not reactive, water soluble, excretable, and has been catalyzed by transferases (conjugated).

THE ENZYMES OF BIOTRANSFORMATION Organs involved in biotransformation: o Liver Parenchymal cells = hepatocytes o Lung Clara cells, type 2 alveolar cells o Kidney proximal tubular cells o Intestine (enterocytes the gut flora) o Skin epithelial cells o Testes seminiferous tubules.

Phase 1: Small molecular weight changes hydroxylation, reduction, hydrolysis etc Generally phase 1 prepares the xenobiotic for phase 2 Cytochrome p450 o Can metabolize many xenobiotics Broad substrate specificity o Widely distributed among tissues o Exist in multiple forms (determined by genes) o Levels can be increased by exposure to chemicals in the food, water or air. THE MULTIPLE FORMS OF CYTOCHROME P450

PHASE 2 METABOLISM Involves the conjugation of xenobiotics with relatively large and highly water-soluble adducts to form glucuronides, sulfates and glutathione adducts. 4 primary enzyme o 1. Glucuronosyltransferase Glucuronic acid o 2. Sulfotransferase Sulfate o 3. Glutathione-S-transferase Glutathione o 4. Acetyltransferase Acetyl At low doses Sulfation predominates At High doses Glucuronidation predominates

Cytochrome p450 is localized in cellular membranes whereas Phase 2 enzymes are, for the most part, in the cytoplasm of cells

Glutathione-S-Transferase Glutathione adducts are further metabolized in the kidney to derivatives referred to as mercapturic acids of the associated xenobiotic mercapuric derivatives are found in the urine Glutathione adducts are excreted in the bile and feces unchanged Some chemicals are reactive enough to form glutathione adducts without GSH transferase

Factors that affect xenobiotic biotransformation Species, strain, and genetic variation o Hexobarbital (barbiturate with hypnotic and sedative effect before anastetic) o Aflatoxin B1 naturally occurring mycotoxins produced by toxins (one of the most carcinogenic substances known) o Benzopyrene 7,8-dihydrodiol (polycyclic aromatic carbon found in coal tar(after forest fire) cigarette smoke, wood smoke and burnt food interfere with transcription o Isoniazid (first line mediciation in treatment of tuberculosis when metabolized in the liver give ammonium and cause hepatits Age Diet Exposure to other chemicals