ACMT Board Review 2012: Molecular Mechanisms 1.3 Apoptosis: Programmed Cell Death Homeostatic...
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ACMT Board Review 2012: Molecular Mechanisms
Russ Kerns, MD, FACMT Carolinas Medical Center
Charlotte, NC
Objectives: Cover Core Content
1.2 Molecular components/mechanisms 1.2.1 Glycolysis & oxidative phosphorylation 1.2.2 Other metabolic pathways (β-oxidation) 1.2.4 Transport proteins (hemoglobin) 1.2.5 Channels
1.3 Cytotoxic mechanisms Provide key example toxins
1.2.1 Glycolysis & Oxidative Phosphorylation
Oxidative Phosphorylation
Energy is released when ATP → P + ADP Restoration of ATP (energy stores) involves
phosphorylation of ADP via coupling of oxidation of H+ to form H20.
Oxidative Phosphorylation
carbohydrate/fatty acid
acetyl-CoA
TCA
NADH/FADH2
electron transport chain
H+ + e-
P
ADP ATP H2O ADP antiporter
H+
e- + O2- + H+
ATP synthase
H+ H+
Main carb metab path Cytosolic process 6C cmpd → 2 X 3 C cmpd Net 2 ATP molecules Make pyruvate for Kreb’s
Glycolysis glucose
glucose-6-P
fructose-6-P
glyceraldehyde-3-P + DHA-P
2 [pyruvate]
fructose-1,6-diP
2 [glyceraldehyde-3-P]
2 [1,3-diphosphoglycerate]
2 [P intermediates]
ATP
ATP
ATP
ATP
Arsenic (V) Substitutes for P Fail to make 1,3-diP intermed Fail to make ATP Fail to make pyruvate
Glycolysis: Toxins
glyceraldehyde-3-P + DHA-P
2 [glyceraldehyde-3-P]
2 [1,3-diphosphoglycerate]
2 [P intermediates]
ATP
2NAD+ + 2 P As5+ X
Glycolysis
CH3CO-CoA acetyl-CoA
NADH
CH3COCOOH
CoA, NAD+
CH3CH2OCOOH
NAD+
lactate
pyruvate
NADH, CO2
Glycolysis: Toxins
CH3CO-CoA acetyl-CoA
CH3COCOOH
lipoamide
pyruvate
dihydrolipoamide
As3+
X
Kreb’s TCA Cycle pyruvate acetyl-CoA
NADH NAD+
citrate
Succinyl-CoA
oxalosuccinate
isocitrate
oxaloacetate
succinate
maleate cis-aconitate
α-ketoglutarate
fumarate
NAD+
NADH
NAD+ NADH
FADH FADH2
Kreb’s TCA Cycle: Toxins
Rodenticides Sodium monofluoroacetate Fluoroacetamide
acetyl-CoA
fluorocitrate
isocitrate
oxaloacetate
cis-aconitate monofluoroacetate
fluoroacetamide
Electron Transport Chain Mitochondrial process Series of oxidation-reduction reactions
Cytochrome enzymes FADH2 and NADH electron sources Produce H2O and ATP
ETC: Toxins Enzyme inhibitors Uncouplers
X X
cytochrome oxidase aa3 NADH-CoQ reductase
X
Cytochrome Oxidase Inhibitors
acetyl CoA
lactate
glucose
pyruvate
TCA cycle
ATP H +
e- transport X X X
lactate
lactate lactate
lactate
lactate lactate
lactate
ETC: Toxins Uncouplers
Salicylate Dinitrophenol (explosives & wood preservative) Pentachlorophenol (fungicide)
Cytochrome aa3 inhibitors Cyanide H2S CO Methanol Phosphine gas Sodium azide (propellant in airbags)
NADH-CoQ reductase Rotenone (plant derived fish poison)
1.2.2 β-Oxidation of FFA
fatty acyl-CoA
CoA carnitine
fatty acylcarnitine fatty acyl-CoA
carnitine-palmitoyltransferase
CoA
(CH)nCO-CoA (CH)n-2CO-CoA + CH3CO-CoA acetyl-CoA
NADH, FADH2
CoA
(CH)nCOOH (CH)nCO-CoA acyl-CoA synthetase
ATP
fatty acyl-CoA
ADP + P CoA
β-Oxidation of FFA: Toxins
fatty acyl-CoA
CoA carnitine
fatty acylcarnitine fatty acyl-CoA
CoA
(CH)nCO-CoA (CH)n-2CO-CoA + CH3CO-CoA acetyl-CoA
NADH, FADH2
CoA
etoh, hypoglycin
valproate
β-Oxidation of FFA: Toxins ↑ NADH/NAD+ ratio
ethanol Hypoglycin(?)
Carnitine Valproate
Undefined mechanism Aflatoxin Amiodarone cereulide dimethylformamide tetracycline
www.australianprescriber.com
Mitochondrial DNA: NRTIs
Nucleoside reverse transcriptase inhibitors Mechanism
Inhibit mitochondrial DNA replication Inhibit ADP/ATP antiporter(?)
Result Lactic acidosis ± steatosis
Agents Stavudine Didandosine Zalcitobine Zidovudine Tenofovir (nucleotide)
X
1.2.4 Transport Proteins
Hemoglobin iron-based tetrameric protein α- and β-globin chains (2 each) Heme complex in each chain (4 total)
protoporhyrin ring central iron atom
Hemoglobin: Toxins
Site of action of toxins Heme synthesis Erythropoiesis Hemorrhage Oxidant stress Competition for oxygen binding
Heme Synthesis: Direct Toxin
Harrison’s On-Line
Heme Synthesis: Indirect Toxins
Acute Intermittent Porphyria Hepatic Autosomal dominant Reduced HMB synthase activity Some drugs may exacerbate AIP by
increasing ALA-synthase activity Poorly defined mechanism
Heme Synthesis: AIP
Barbiturates Carisoprodol Danazol Ethchlorvinyl Meprobamate Primidone Pyrazolones Trimethadione
dark red urine
www.porphyriafoundation.com
Hemoglobin: Toxins
Erythropoiesis Nephrotoxins - ↓ erythropoietin Pure rbc aplasia – rare
INH Hypoglycemics (chlorpropamide, tolbutamide) Phenytoin Sulfasalazine Valproate (single case report)
Hemoglobin: Aplastic Anemia aplastic marrow normal marrow
www.hopkinsmedicine.org
Hemoglobin: Aplastic Anemia
Immune mediated T lymphocytes release cytokines
Suppress hematopoietic stem cells Apoptosis (↑ Fas receptors on stem cells)
TNF
interferon-γ
Hemoglobin: Aplastic Anemia
DNA injury Direct DNA injury
Ionizing radiation Inhibition of DNA replication
Folate inhibitors (methotrexate) Intermediary metabolite that binds DNA
Benzene (quinone + free radicals) Tubulin inhibition during cell replication
Antimitotics (colchicine, vincristine, vinblastin)
metaphase arrest
metaphase.wordpress.com
Hemoglobin: Aplastic Anemia Antibiotics
Chloramphenicol Anti-convulsants
Carbamazepine, phenytoin Anti-inflammatory agents
Diclofenac, D-penicilamine, gold salts, indomethicin, phenylbutazone
Anti-neoplastic agents Alkylating agents (nitrogen mustards) Antibiotics (danorubicin, adriamycin) Antimitotics (colchicine, vinblastin, vincristine) Antimetabolites (purine and pyrimidine analogues)
Antipsychotics Chlorpromazine, clozapine
Hemoglobin: Aplastic Anemia Chemicals
Benzene, lindane Metals
Arsenic Miscellaneous
Acetazolamide, captopril, cimetidine, chlorpromazine, dapsone, fluoxetine, meprobamate, nifedipine, PTU, ticlopidine, tocainide
Radiation
Hemoglobin: Toxins
www.pathology.vcu.edu
Hemoglobin: Toxins
Megaloblastic anemia ↓ Vit B12 absorption
Colchicine, metformin, neomycin ↓ folate absorption
Etoh Impaired dihydrofolate reductase
Methotrexate Pyrimethamine Pyridium Trimethoprim
Hemoglobin: Oxidant Stress
Heme: deoxyhgb → Methgb (Fe2+→Fe3+) Prophyrin ring by sulfur: Sulfhgb Globin: Heinz body hemolytic anemia
Hemoglobin: Oxidant Stress
Protection from oxidant stress Ascorbic acid (Vit C) Glutathione (intact HMP, G6PD) Enzymatic
NADH-dependent reductase (Cytochrome b5 reduc) NADPH-dependent reductase (intact HMP, G6PD) Catalase Hydrogen peroxidase
Hemoglobin: Methemoglobin
Fe2+ state: deoxyhemoglobin carries oxygen