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Chemicals introduced into living systems where they are normally foreign Therapeutic drugs, non-nutritive constituents of food, man-made chemicals, solvents, pesticides, pollutants Basic to a rational understanding of pharmacology and therapeutics, pharmacy, toxicology, cancer research and drug addiction Absorption: oral, inhalation, topical, IM, SC, IP, IV (most direct) Route: Absorption (into blood), distribution (into other tissues), metabolism (into metabolites) and excretion (urine, etc.)

Biotransformation / Xenobiotic Metabolism  Conversion of potentially dangerous substances to inactive and excretable forms  At least 30 different enzymes systems

Liver as the main site of metabolism, kidneys and lungs as 2° organs NOT detoxicification

Phase I

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Functionalization – conversion of xenobiotics into polar derivatives  inactivate or activate Hydroxylation – main reaction o Catalyzed by monooxygenases or Cytochrome P450s; requires O2 and NADPH

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Mixed function oxidases  Dual fate of oxygen – 1 atom becomes water, another becomes OH

Cytochrome P450 Most important and versatile Phase I catalyst; metabolizes more than 50% of all drugs and chemicals Microsomal (membrane-bound); Monooxygenases or aromatic hydrocarbon hydroxylases Characteristics 1. Large number of isoforms – more than 150; 30 in humans (8-10 prominent)

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hemoprotein – heme moiety as central site of action, strong absorption at 450 nm when with CO widely distributed among different species – bacterial / mitochondrial (Type I), microsomal (Type II) highest in liver, in SER membrane – small amounts in mitochondria and hepatocyte nuclear membrane, as well as adrenal cortex and testes multiple isoforms with wide and overlapping substrate specificity

5. 6. NADPH-requiring – NADPH-CytP450 reductase wish NADPH reduces CytP  oxygen atom into substrate 7. has lipids – phophatidylcholine, present in ER membranes 8. most isoforms are inducible – phenolbarbital = ↑ warfarin metabolism; ethanol = induces CYP2E1 = cancer 9. metabolism of polycyclic aromatic hydrocarbons – PAHs are procarcinogenic 10. polymorphism – lower or higher catalytic activity in different people; CYP2D6 – debrisoquine metabolism  

Other reactions catalyzed by CytP450 – arene oxide formation, epoxidation, desuliuration and sulfoxidation, deamination and Nhydroxylation, azo, nitro and hydroxylamine reduction, carbonyl reactions Other Enzyme systems catalyzing other Phase I reactions – amine oxidase, epoxide hydratase (esterases), amidases, OH DH Nomenclature o Sample cytochrome: CYP1A2 o CYP = cytochrome o A = Subfamily (same if >55% AA homology) o 1 = Family (same if >40% AA homology) o 2 = individual number Inducers o Chemicals: alcohol, chlordane, chloroform, DDT/DDD

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Drugs: barbiturates, ethanol, nicotine, steroids, isoniazid, rifampicyn PAH: benzopyrenes, dibenzanthracene, 3-methylcholanthrene

Inhibitors – via (1) competitive binding, (2) synthesis inhibition, or (3) inactivation or destruction of CytP450 or ER o Chloramphenicol, carbon tetrachloride, bromobenzene Factors affecting Biotransformation o Diet and nutrition – starvation, low protein intake, mineral and vitamin deficiencies = ↓ metabolism / inhibit

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Phase II

Hormonal – ACTH, GH, thyroid hormones, glucocorticoids, anabolic steroids = ↑ metabolism Age and Sex – neonates and elderly = ↓ metabolism Genetic - variation Pathological – modification of absorption, distribution, and excretion; alter nutritional state and rate of blood and oxygen delivery to liver

Polarization of Phase I derivatives via conjugations  water-soluble Can also activate some xenobiotics instead of inactivating them Process Donor Enzyme Glucuronidatio UDP-glucuronic acid glucuronosyltransferase n Adenosine 3’-PO4Sulfation 5’-phosphsulfate (PAPS / active sulfate) Conjugation Glutathione-SGSH (cysteinyl moiety) with GSH transferase Acetylation acetylCoA Acetyltransferase Methylation S-adenosylmethionine (SAM) methyltransferase Cellular Response  Between Phase I and II – xenobiotic becomes reactive metabolite 

Notes Most common, In ER and cytosol; for aniline, phenols, 2-acetylamhtofluorine, benzoate, steroids For alcohols, arylamines, phenols Important defense against electrophilics; Gly and Glu removed  Cys is N-acetylated (N-mercapturic acid) isoniazid (INH) slows acetylators

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Reactive metabolite + macromolecules via covalent reaction Cytotoxicity – cell death and injury, targets DNA, RNA, CHONs o Bioactivation of parathion, acetylcholinesterase, acetaminophen, paracetamol Antibody Production – acts as hapten (proantibody)  antibody against self (immunologic damage) o Co-trimoxazole in Steven-Johnson Syndrome (skin disease, toxic epidermal necrolysis) Chemical Carcinogenesis – metabolite + DNA = carcinogenesis o Benzopyrenes

 Alcohol affects virtually the whole body <10% of ethanol excreted in breath, sweat and urine 90% via oxidation, mostly in liver Not storable in liver No major feedback mechanisms to pace rate of metabolism

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Ethanol  Equilibrium conc depends on relative water content

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Insoluble in fat and oil Can pass membranes No plasma protein for transport Absorption o Concentration – passive diffusion

Food – ↓ absorption, more in jejunum and ileum Excretion Factors o Sex – females faster

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Type – ethanol concentration Blood flow @ Absorption site - ↑ flow = ↑ absorption Rate of ingestion – faster = ↑ absorption

Age – extremes slower Race – highest in Native Americans, lowest in African Americans

Food - ↑ CHO = faster (Fructose effect: help convert NADH to NAD) Oxidation o Ethanol + ADH  acetaldehyde + ALDH  acetic acid  aCoA  CO2 / FA / ketone bodies / cholesterol o ↑ ethanol = ↑ NADH = ↓ Krebs = ↑ FA synthesis = fatty liver

Acetaldehyde Metabolism

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Reactive, interacts with thiol and amino groups of CHON = adduct formation  mutagenesis (with nucleic acids) or cytotoxicity (with CHON) Microsomal Ethanol Oxidation System (MEOS): converts ethanol into acetaldehyde CYP2E1 – highest activity; inducible; Km 10x higher than ADH = more active @ ↑ ethanol conc

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