Metabolism of xenobiotics Seminar No. 8 Q. 2 1. Phase of biotransformation = mainly oxidations Q. 3 A. 3 Q. 4 + 5 A. 4 + 5 Hydroxylation Q. 6 A. 6 • Inducer may act on several levels: • Inducer in complex with intracellular receptor enters nucleus and binds to DNA TH enhances the transcription of mRNA • Decreases the degradation of mRNA and/or CYP • Influences the poststranscription modifications of mRNA • May cause the hypertrophy of ER Influence of CYP inducers/inhibitors on the effect of drug (remedy) Q. 7 A. 7 • if concurrently aplied inducer + medicament metabolized with the same CYP isoform TH remedy is catabolized faster TH is less effective • diclofenac is less effective Q. 8 A. 8 • if concurrently aplied inhibitor + medicament metabolized with the same CYP isoform TH remedy is catabolized more slowly TH higher concentration in blood  adverse effects (overdosing) Q. 9 A. 9 - II. Phase of biotransformation • conjugation – synthetic character • xenobiotic after I. phase reacts with conjugation reagent • the product is more polar – easily excreated by urine • conjugation reactions are endergonnic – they require energy • reagent or xenobiotic has to be activated A. 9 Overview of conjugation reactions A. 9 Overview of conjugation reactions PAPS is sulfatation reagent phospho adenosine phospho sulfate The conjugation reactions of phenol Glutathione (GSH) Conjugation with aminoacids • glycine, taurine • xenobiotics with -COOH groups • the products of conjugation are amides • endogenous substrates – bile acids Biotransformation of toluene (sniffers) Ethanol How can you calculate the level of alcohol in blood? Per milles of alcohol in blood m[alcohol] is calculated from volume and density Metabolism of ethanol Write AD and AcD reactions Alternative pathway of alcohol biotransformation occurs in endoplasmic reticulum Q. 11 A. 11 Acetate is converted to acetyl-CoA • in liver TH synthesis of FA ® TAG  VLDL • in other tissues TH CAC ® CO[2] + energy Q. 14 A. 14 Q. 15 A. 15 • Decreased gluconeogenesis due to lack of oxaloacetate – hypoglycemia especially after fasting ingestion of alcohol (+ usually poor dietary habits in chronic alcoholics) • Excess of lactate in cytosol TH increased lactate in blood plasma  lactic acidosis • Excess of acetyl-CoA  synthesis of FA +TAG  liver steatosis Consider that • ethanol is soluble both in polar water and non-polar lipids • easily penetrates cell membranes • goes through hydrophilic protein channels or pores • as well as hydrophobic phospholipid bilayer Metabolic consequences of EtOH biotransformation Acetaldehyde reacts with biogenic amines to tetrahydroisoquinoline derivatives Nicotine - the main alkaloid of tobacco Cigarette smoke contains a number of different compounds • free nicotine – binds to nicotine receptors in brain and other tissues • CO – binds to hemoglobin ® carbonylhemoglobin • nitrogen oxides – can generate free radicals • polycyclic aromatic hydrocarbons (PAH) (pyrene, chrysene), main components of tar, attack and damage DNA, carcinogens • other substances (N[2], CO[2], HCN, CH[4], terpenes, esters …) Biotransformation of nicotine Biochemical markers of liver diseases Biochemical markers of liver diseases Selected biochem. markers of liver damage (in serum)