IV: Mitochondrial Function cont d. HEPATIC DETOXIFICATION OF a monoamines, liquor, toluene b dietary or endogenous pu

0
0
2109 days ago, 661 views
PowerPoint PPT Presentation
2. . Detoxification of monoamines catalyzed by mitochondrial external layer MAO. . R-CHNH2. . . . O2. H2O2. R-CH=NH. . . NH3. R-CHO. . R-COOH. . b-oxidation. CO2. . ATP, HCO3-. UREA. urea cycle. . MONOAMINE OXIDASEFlavin-containing amine oxidase. (imine). . inward layer. . external film.

Presentation Transcript

Slide 1

IV: Mitochondrial Function (cont'd). HEPATIC DETOXIFICATION OF a) monoamines, liquor, toluene b) dietary or endogenous purines (meat), heme (red meat) & bilirubin,

Slide 2

Detoxification of monoamines catalyzed by mitochondrial external film MAO e.g., dopamine norepinephrine tyramine phenethylamine octylamine serotonin external layer MONOAMINE OXIDASE Flavin-containing amine oxidase R-CHNH 2 inward layer R-CH=NH (imine) O 2 NH 3 H 2 O 2 R-CHO NAD + ATP, HCO 3 - aldehyde dehydrogenase urea cycle UREA NADH R-COOH b - oxidation CO 2 Mitochondrion

Slide 3

Amine specificity for the two isoforms (A & B) in people MAO A specially metabolizes serotonin. MAO B specially metabolizes phenethylamine, dopamine. MAO inhibitor + dietary amines or restrictive medications MAOB inhibitor deprenyl ( selegiline) like phenethylamine and expands mind dopamine levels. This is utilized to treat Parkinson's sickness. In any case, " Hypertensive emergency " is a hyperadrenergic state prompted by MAO inhibitors + pressor amines (e.g., tyramine in cheese,beer,wine or soya sauce) or exclusive medications (e.g., L-DOPA , mazindol, ephedrine, and so forth). Perry, 1996. http://www.vh.org/grown-up/supplier/psychiatry/CPS/19.html

Slide 4

Detoxification of alcohols by framework ALDH2 Covalently ties to protein-NH 2 (ADH) cytosolic liquor dehydrogenase acetaldehyde ETHANOL ANTABUSE (disulfiram) or cyanamide NADH NAD + Methyl pyrazole NAD + aldehyde dehydrogenase CO 2 NADH (ALDH) TCA cycle ATP acetic acid derivation acetylCoA CoASH

Slide 5

COOH URINE CONHCH 2 COOH Hippuric corrosive c) Benzoic acidosis instigated by toluene stick sniffing Benzaldehyde Toluene Benzyl liquor ADH Cyt P-450 CH 3 CH 2 OH CHO CYTOSOL ER ALDH1/ALDH2 MITOCHONDRIA Benzoic corrosive Benzoyl-CoA synthetase ATP CoA N-acyltransferase Benzoyl-CoA glycine 5 Teratogen Update: Toluene teratology. 55, 145-51, (1997)

Slide 6

8. Hemoprotein poisonous quality infections brought about by heme or bilirubin A) Rhabdomyolysis (tranquilize actuated) discharges myoglobin and heme and causes kidney mitochondrial harm B) Kernicterus:- bilirubin causes neonatal mind mitochondrial harm

Slide 7

A) M yoglobin interceded rhabdomyolysis once in a while created by statins STATIN Drug BAYCOL pulled back by BAYER, 2001 CRUSH INJURY Or if LAIN IMMOBILE for hrs (e.g. EtOH, warm stroke) Muscle Cell Drug receptive metabolites Mitochondrial/cytotoxicity x10  creatine phosphokinase Dark cocoa granular throws in pee Myoglobin discharge Massive muscle breakdown Acid Mb Fe aggregates in kidney renal tubule Acid lipid peroxidation (proximal tubule) mitochondrial lethality KIDNEY Failure (7% of all instances of intense renal disappointment) Spontaneous myalgias Muscle delicacy, Weakness, disquietude, fever DEATH THERAPY 1.) NaHCO 3 base 2.) Desferoxamine CMAJ 165(5) pg 632 (2001); J. Biol. Chem. 273, 31731-7 (1998)

Slide 8

B) Hemoglobin/heme interceded mind harm ie. Kernicterus (mind harm brought about by bilirubin in the infant (hyperbilirubinemia)) re-development ( because of shorter clinic time, breastfeeding) threat signs onset of jaundice 3 days taking after birth, regurgitating, dormancy, poor encouraging, fever, sharp crying. plasma bilirubin > 340 uM = trade transfusion treatment plasma bilirubin > 240 uM = Phototherapy (blue light) Drug treatment Sn protoporphyrin (hinders heme oxygenase). Hemoglobin Bilirubin ties to discharged mind mitochondrial serum egg whites by contending harmfulness (hearing unsaturated fats or misfortune? mind harm drugs encephalopathy) Heme oxygenase of reticuloendothelial cells of spleen, liver, kidney Glucuronyl Transferase Appears at 7d after birth Glucuronide conjugated bilirubin. 0.3% mortality (yellow recoloring of cerebrum) family history, hemolytic ailments, Gilbert's illness, diabetes (erythrocyte delicacy), G6PD insufficiency (Pediatrics 106, 1478-80 (2000), sickle cell.

Slide 9

Metabolic pathway of heme corruption to bilirubin and detoxification of bilirubin by glucuronidation. (M=methyl,V=vinyl and P=propionate speak to heme side chains CO Fe 2+ Heme Oxygenase NADPH: P450 Reductase NADPH NADP + NADPH O 2 NADP + H 2 O NADPH Biliverdin Reductase NADP + UDP-glucuronic corrosive UDP-glucuronosyl transferase JAUNDICE Antioxidant, however at high concn. Dangerous TO NEONATAL BRAIN MITOCHONDRIA

Slide 10

9. HEME BIOSYNTHESIS BY MITOCHONDRIA AND GENETIC DISEASES A) Heme biosynthesis for cytochromes, and so on. B) Genetic maladies: Porphyrias and porphyrin poisonous quality C) Oxidative debasement of heme to bilirubin

Slide 11

A) HEME BIOSYNTHESIS and porphyria illnesses

Slide 12

Cytochrome Heme Synthesis - Overall picture

Slide 13

Heme union Heme required for amalgamation of mitochondrial cytochromes and endoplasmic reticular P450s. Heme required for bone marrow amalgamation of hemoglobin and muscle myoglobin STEP 1 for heme combination is the union of aminolevulinic corrosive (ALA) from succinyl CoA of the citrus extract cycle and glycine

Slide 14

Heme biosynthesis in bone marrow (hemoglobin) and liver (cytochromes) NH 2 or lead 1

Slide 15

Erythropoietin integrated by kidney actuates hemoglobin union in bone marrow (replaces blood transfusion!)

Slide 16

Heme Biosynthesis - STEP 2 in the cytosol (4 compounds 2-5) 1

Slide 17

Heme Biosynthesis - STEP 3 - mitochondrial last strides (3 catalysts)

Slide 18

B) PORPHYRIAS I. Chemicals Inhibitors bringing about porphyria II. Hereditary porphyrias

Slide 19

I. Catalyst INHIBITORS CAUSING PORPHYRIA - Greek "porphyros" (purple pee) an over-creation malady. Regularly neuropsychiatric (syphilis a great deal more so). 2) ALA dehydratase - lead 5) Uro'gen decarboxylase - PCBs, dioxin, lead, cadmium, hexachlorobenzene (fungicide - seeds). Mitochondrial oxidase - steroids (conception prevention pills) and estrogens 8) Ferrochelatase – lead II. Hereditary PORPHYRIAS (Emerg Med Clin.N Am 23 (2005)885-899) 2) ALAD insufficiency porphyria (Seminars in Liver Disease, 18, 95-101, 1998) discharge ALA not PBG, side effects like  (neurological).

Slide 20

Scriber et al. (eds). Metabolic and atomic premise of acquired sickness. seventh ed. 1995, p.2124.

Slide 21

3) Acute irregular porphyria (i.e. phosphobilinogenin deaminase insufficiency) discharge ALA and PBG , the most well-known hepatic porphyria)- MEDALERT arm ornament 1. Side effects - discharge PBG and ALA in the pee , high plasma PBG/ALA - extreme stomach torment , sickness, retching, hypertension(cardiovascular) then CNS - tension, sleep deprivation, perplexity, pipedream, distrustfulness then fringe neuropathy - deadly respiratory loss of motion. Liver growth . 2. a. PBG deaminase insufficiency - quality locus 11q24 (>100 transformations), autosomal predominant 1:10,000-50,000 however 1:1000 in N. Sweden (Lapland) b. Accelerated by phenytoin, phenobarbital drugs, liquor, fasting, hormones estrogen, stress, disease or lead harming 3. Natural chemistry of neurotoxicity a. heme lack   P450 tranquilize digestion system   tryptophan dioxygenase mind tryptophan  cerebrum serotonin mitochondrial cytochromes (mitoch.disease) b.  ALA  "ROS", mitochondrial DNA harm. 4. Treatment –  ALA with heme arginate (taken up by liver not b.m.), high glucose 5. Mouse display (PBG knockout) - called Vincent! - behavioral reviews Suspects - Van Gogh, King George III(?) (Absinthe for sleep deprivation) 6.Diagnosis :- Patients pee introduction to daylight (rosy cocoa fluorescence)

Slide 22

4) Congenital erythropoietic porphyria (Erythroid, Photosensitive) - Fe over-burden of b.m., uroporphyrin over-burden of skin and erythrocytes  hemolysis 1. Indications: skin injuries (light) , danger of contamination in early stages Anemia (hemolysis) Teeth ruddy chestnut (fluorescence) 2. Uroporphyrinogen III synthase inadequacy Uroporphyrinogen I and coproporphyrin I collection in the skin, bone marrow, erythrocytes, pee, plasma 3. Treatment: enacted charcoal (oral); b.m. transplant; quality treatment for bone marrow; blood transfusion to stop erythropoiesis in b.m. 4. Just 200 analyzed up until this point; werewolf, vampires (early youth delicate to light skin rankles, disease  distorts) is not porphyria

Slide 23

5) Porphyria Cutanea Tarda - "heme insufficiency and uroporphyrin over-burden of liver" (Photosensitive; commonest porphyria;readily treated). 1. Indications: sores on backs of hands and face because of photosensitization by uroporphyrin I, III or uroporphyrinogen. Stomach torment, neural,psychiatric.  ALA,porphobilinogen. 2a. Finding :-  urinary uroporphyrin >> coproporphyrin . b. Uroporphyrinogen decarboxylase lack (liver additionally erythrocyte in sort II): or hexachlorobenzene or dioxin incited CYP 1A2. (Turkey bread calamity). Additionally Fe  uroporphyrinogen III synthase -  uroporphyrin I. c. Applicant hemochromatosis quality prompts to conclusion of hemochromatosis 3. Precip. by liquor , hepatitis C infection, estrogen (anti-conception medication, post-meno-stop, prostate, pregnancy), Fe . 4. Natural chemistry - inactivation of decarboxylase (- SH chemical) by "ROS" from lessened P450/P450 reductase/Fe 5. Treatment:- Fe evacuation (phlebotomy or desferoxamine and ascorbic corrosive) - chloroquine  endocytosis and discharges uroporphyrin chloroquine complex from hepatocytes - heme?

Slide 24

6) Hereditary Coproporphyria - coproporphyrinogen oxidase insufficient, interminable weariness disorder. - hepatic porphyria Symptom

SPONSORS