Metabolic functions of liver (not in seminar book) Catabolism of hem (Chapter 15) Biotransformations of xenobiotics (not in seminar book) Seminar No. 6 - Chapter 15 (partly) - Glucose metabolism in liver * well-fed state (insulin): glycogenesis, glycolysis * fasting (glucagon): glycogenolysis, gluconeogenesis * other pathways: pentose cycle (ribose, other pentoses, NADPH) the isomeration of glucose to galactose the conversion of fructose and galactose to glucose synth. of derivatives: glucuronic acid, glucosamine ..... Aminoacid metabolism in liver * synthesis of most plasma proteins * up-take and degradation of plasma proteins + peptide hormons * catabolism of AA (transamination - ALT, deamination - GMD) * synthesis of non-essential AA * detoxication of ammonia (urea, glutamine) Lipid metabolism in liver * synthesis of FA and TAG * synthesis of phospholipids * synthesis of lipoproteins (VLDL, HDL) * degradation of TAG/PL - CM remnants, IDL, LDL, HDL[2] (hepatic lipase, lysosome) * b-oxidation of FA * synthesis of KB -- for export only succinyl-CoA:acetoacetate-CoA transferase (for activation of acetoacetate) is not in liver Cholesterol metabolism in liver * synthesis of cholesterol * excretion of cholesterol into bile * synthesis of bile acids * conjugation of bile acids * excretion of bile acids into bile The localization of metabolic processes (see also p. 56) Catabolism of hem p. 88 Hem is a chelate of protoporphyrin IX with Fe^2+ Catabolism of hem * occurs mainly in spleen, liver, bone marrow * hemoxygenase (O[2], NADPH, cytochrome P-450) * Fe^2+ is released and oxidized to Fe^3+, bound to ferritin (store) * -CH= between A/B rings is split off as carbon monoxide (CO) * two O atoms are attached to the A+B pyrrole rings (r) biliverdin * the central -C= bridge between C/D rings in biliverdin is then reduced to -CH[2]- bridge (r) bilirubin Hem degradation provides CO and bilirubin Three oxygen atoms attack protoporphyrin Q. What happens with CO in human body? Carbonylhemoglobin (CO-Hb) in blood Text-book structure of bilirubin Q. Why is bilirubin non-polar compound? Properties of bilirubin * linear tetrapyrrol system * free rotation around central -CH[2]- is possible * non-linear conformation arises, stabilized by six intramolecular H-bonds * all polar groups are involved in H-bonds * consequence: free bilirubin is non-polar, insoluble in water, in plasma -- bound to albumin Real structure of bilirubin with six intramolecular H-bonds Q. What is UDP-GlcA? Uridine diphoshoglucuronic acid Conjugation of bilirubin in liver * bilirubin reacts with two molecules of UDP-glucuronate * two highly polar molecules of glucuronate are attached to bilirubin with glycosidic ester bond (r) bilirubin bisglucuronide * conjugated bilirubin is soluble in water (bile, plasma, urine) * conj. bilirubin is excreted with bile into intestine, where it is deconjugated and hydrogenated by microflora (r) urobilinogens, they are partially absorbed by v. portae and taken up by liver Laboratory findings in three types of hyperbilirubinemia Greek word ce'no*s [xenos] means stranger * Xenobiotics do not normally occur in human body * Chemical industry -- produces synthetic compounds which do not occur in nature (plastics, pesticides, pigments, food additives) and various pollutans (as side products) * Pharmaceutical industry -- produces drugs (medications) of synthetic origine or isolated from plants/animals/fungi/bacteria Biotransformation of xenobiotics in cells * two phases of biotransformations * xenobiotics becomes more polar * they are easily excreted from body (urine, bile - stool) I. Phase of biotransformation Enzymes of I. phase are rather non-specific * great advantage for human body !! * monooxygenases (cytochrome P-450) * flavine monooxygenases * peroxidases * hydrolases * alcoholdehydrogenases and other ... Cytochrome P-450 (CYP) * the group of hem enzymes (cca 150 isoforms) * many of them are inducible * occur in most tissues (except of muscles and RBC) * mainly in liver Mechanism of cytochrome reaction * CYP catalyzes hydroxylation (R-H (r) R-OH ) [* ] substrate reacts with O[2 ]* monooxygenase = from O[2] one atom O is inserted into substrate (between carbon and hydrogen atom) ^* the second O atom makes H[2]O, 2H come from NADPH+H^+ [* ] dioxygen is reduced to -OH group and water General scheme of hydroxylation A more detailed scheme of hydroxylation Main isoforms of cytochrom P-450 Induction and inhibiton of CYP 450 * some xenobiotics trigger induction of CYP synthesis TH metabolic capacity of CYP increases * if concurrently aplied inducer + medicament metabolized with the same CYP isoform TH remedy is catabolized faster TH is less effective ------------------------------------------------------------------------------- * some xenobiotics are inhibitors of CYP * if concurrently aplied inhibitor + medicament metabolized with the same CYP isoform TH remedy is catabolized more slowly TH higher concentration in blood TH adverse effects/overdosing Biotransformation of benzene Biotransformation of polycyclic aromatic hydrocarbons (PAH) 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 Overview of conjugation reactions Biosynthesis of UDP-glucuronate The structure of UDP-glucuronate Glucuronides are the most abundant conjugates * O-glucuronides ether type (Ar-O-glucuronide, R-O-glucuronide) ester type (Ar-COO-glucuronide) * N-, S-glucuronides * exogen. substrates: arom. amines, amphetamines, salicylic acid, drugs, flavonoids ... * endogenous substrates: bilirubin, steroids Biotransformation of amphetamine PAPS is sulfatation reagent phospho adenosine phospho sulfate The conjugation reactions of phenol Glutathione (GSH) Mercapturic acids are final products of GSH conjugation Conjugation with aminoacids * glycine, taurine * xenobiotics with -COOH groups * the products of conjugation are amides * endogenous substrates -- bile acids Biotransformation in toluene sniffers Main path of ethanol biotransformation occurs in liver cytosol Alternative pathway of alcohol biotransformation occurs in endoplasmic reticulum Q. What are the main metabolic consequences of ethanol metabolism? Metabolic consequences of EtOH biotransformation 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 (see page 135) * CO -- binds to hemoglobin (r) 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 Main pathways of paracetamol biotransformation Side pathway of paracetamol biotransformation leads to hepatotoxic quinonimine Biotransformation of acetylsalicylic acid Selected biochemical markers of liver damage