Biotransformation and Elimination of Toxicants

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Explain the role of biotransformation in toxicokinetics. • Describe how biotransformation facilitates elimination of toxicants. • Distinguish between Phase I and Phase II reactions. • Define bioactivation or toxication.

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Nội dung Text: Biotransformation and Elimination of Toxicants

Principles of Environmental Toxicology Learning Objectives • Explain the role of biotransformation in toxicokinetics. • Describe how biotransformation facilitates elimination of toxicants. Biotransformation and Elimination • Distinguish between Phase I of Toxicants and Phase II reactions. • Define bioactivation Principles of Environmental Toxicology or toxication. Instructor: Gregory Möller, Ph.D. University of Idaho 2 Principles of Environmental Toxicology Principles of Environmental Toxicology Learning Objectives, 2 Metabolism • Sum of biochemical rxns occurring to a • Identify tissues and factors molecule within the body. involved in biotransformation. – Anabolism - “build-up” • Summarize the role of elimination in – Catabolism - “break-down” toxicokinetics. • Occurs in the cytoplasm or • Describe processes occurring in at specific organelles within the kidney, liver and lung the cell. related to the elimination • Storage affects the body’s of toxicants. ability to biotransform and eliminate. – Bone, lipid. 3 4 Principles of Environmental Toxicology Principles of Environmental Toxicology Biotransformation Biotransformation Reactions • Process that changes substances from hydrophobic • Grouped as Phase I (functional group modification) to hydrophilic to aid in elimination (grease to salt). and Phase II (conjugation). – Hydrophilic molecules are less able to cross cellular • Goals membranes, hence fluid filterable (kidneys). – Produce water soluble metabolites. – Major elimination routes are – Activate natural/endogenous compounds feces (biliary) and urine. for normal function. – Biological half-life, T½ • Some compounds undergo allows comparison of bioactivation. rates of removal. – The biotransformed metabolite is more toxic than the original compound. 5 6 1
Principles of Environmental Toxicology Principles of Environmental Toxicology Results of Biotransformation Major Categories/Reactions • Increase toxicity via a toxic metabolite. Phase I • Decrease toxicity via metabolism of a toxic oxidation parent compound. reduction • No effect on toxicity. hydrolysis • Present to metabolize endogenous compounds. Phase II polar conjugation synthesis very polar Elimination 7 8 Principles of Environmental Toxicology Principles of Environmental Toxicology Enzymes of Biotransformation Phase I Reactions R NHOH Phase I Enzymes R NH2 N-oxidation Hughes • Oxidation (most important). R1 R1 S – Add O, remove H, increase valence. S O S-oxidation R2 R2 – Cytochrome P-450, MFO, alcohol dehydrogenase, O OH oxidases, others. C R1 CH R1 Carbonyl reduction • Reduction (less important). R2 R2 – Remove O, add H, decrease valence. O R2 – Reductases. CH2OOH + HO R1 R1 C-O R2 Ester Hydrolysis • Hydrolysis. R1 R1 – Add water. C S C O Desulfuration – Esterases, phosphtases, others. R2 R2 9 10 RCH2OH RCHO Dehydrogenation Principles of Environmental Toxicology Principles of Environmental Toxicology Enzymes of Biotransformation, 2 PII Cofactors: GSH Phase II Enzymes NH2 O • Conjugation reactions. H O HO N • Enzymes (tranferases) + cofactor. N – Enzyme catalyzes. H OH O O – Cofactor donates group. HS – Glucuronic acid, glutathione, sulfate, acetyl group, methyl group. – Tends to increase molecular size and Glutathione polarity for excretion. 11 12 2
Principles of Environmental Toxicology Principles of Environmental Toxicology PII Cofactors: Acetyl-CoA PII Cofactors: PAPS OO NH2 HO OH P P N 3’-Phosphoadenosine O Acetyl Coenzyme A O O N 5”-phosphosulfate O O N O N N N N O O HO NH O P OH HO O N HO NH2 O S O P O O OH OH NH OH O O P OH S OH 13 14 O Principles of Environmental Toxicology Principles of Environmental Toxicology PII Cofactors: UDPGA Benzene Metabolism O H HO H UDP-GT Glucuronide OH HO Uridine-5’- Phenol diphosphoglucuronic acid N H ST OSO3 O H PAPS O N O H H2C OH O P OH Epoxide P450 HO O O Epoxidation Hydratase P OH O Toxic Epoxide Dihydrodiol H O H OH HO H GSH GST HO O OH H O H - O 15 16 Glutathione Principles of Environmental Toxicology Principles of Environmental Toxicology Aniline De-Alkylation Phase II H NH2 N P450 OH Phase II O H P450 N N + HC Amine N-hydroxylation Dimethyl-propyl-amine Acetaldehyde Methyl-propyl-amine 17 18 3
Principles of Environmental Toxicology Principles of Environmental Toxicology Case Study: Fluorocitrate and Kangaroos Free Radical Generation • Fluorocitrate found in legume NADH Cl pasture plants Cl P450 of Western Australia. Cl C Cl Cl C GSH – Gastrolobium and Oxylobium. Reducatase Cl Cl • Highly lethal (TD 1 mg/1080 kg). Toxic Free Radical Tetrachloro-methane WACALM – Leaf concentrations can be 2.6 g/kg. • The rat and gray kangaroo of Western Australia have evolved resistance. – In vivo defluorination w/ glutathione. – Other kangaroos from areas w/o these plants are not tolerant. Harborne 19 20 Principles of Environmental Toxicology Principles of Environmental Toxicology Rodenticide: Fluoroacetic Acid Fluorocitrate Metabolite CoASH H O O O AcCoA O OH O OH F C COSCoA F HO O HO OH F H O OH FAcCoA HO Fluoroacetate Fluoroacetyl CoA Sodium Fluoroacetate Compound 1080 rodenticide predator control 21 22 Principles of Environmental Toxicology Principles of Environmental Toxicology Krebs Cycle Deoxynivalenol, Vomitoxin (Fluoro)Citrate O O AcCoA O OH OH OH O OH O O O O HO O HO F O OH FAcCoA Mitochondrial HO HO HO Oxaloacetate energy production HO HO CH2 O H2 O Aconitase Fusarium trichothecene O mycotoxin found on O OH corn and barley O HO Cis-aconitate HO 23 24 4
Principles of Environmental Toxicology Principles of Environmental Toxicology Aflatoxin B1 Benzo[a]pyrene O O H O H O OH O O OR H H O O O O R = sulphate or glucuronic acid O O Q1 = hepatic metabolite B1 • Polycyclic aromatic hydrocarbon. • Environmental carcinogen. Aspergillus mycotoxin • Cell cultures from rodents, found on corn, peanuts fish and humans and cottonseed 25 26 Principles of Environmental Toxicology Principles of Environmental Toxicology Heavy Metal Toxicity - Pb Heavy Metal Toxicity - Pb, 2 • Absorbed via Ca channels as divalent ion. • Sensitivity of a system and degree of interference determines clinical effects. • Capable of reacting with a variety of binding sites. – Digestion/respiration → absorption. – Protein precipitation. – Liver → detoxication. • Specific toxic effect depends on rxns with ligands – Kidney → excretion. that are essential for the living system. • Antidotes are competing ligands. • Metal ligands are formed with sulfhydryl groups, as well as O O OH amino, phosphate, imidazole, HO N and hydroxyl groups of enzymes EDTA and essential proteins. N O HO O OH 27 28 Principles of Environmental Toxicology Principles of Environmental Toxicology Heavy Metal Toxicity - Pb, 3 Heavy Metal Toxicity - Pb, 4 • Some endpoints. SH • Metallic lead absorbed most efficiently – Sulfhydral enzyme inhibition. by the respiratory tract. HO CH SH C C – K transport in RBC inhibited • 10% of ingested lead is absorbed. H2 H2 • Anemia. – Small intestine. 2,3-Dimercapto-propan-1-ol – Porphyrinuria. – Lead salts are soluble in gastric juices; absorbed. • Excreted chiefly in • Plasma to blood cells – erythrocytes. feces and urine. • After oral ingestion: • Chelating agents: – 60% bone (also hair, teeth). – Ca - EDTA. – 25% liver (hepatocytes). – Penicillamine. – 4% kidney (renal tubules). – Dimercaptrol (BAL). – 3% intestinal wall. 29 30 5
Principles of Environmental Toxicology Principles of Environmental Toxicology Case Study: Elevated PbB Associated with Case Study: “Moonshine” Lead Toxicity Illicitly Distilled Alcohol, Alabama 1991 • Seven patients required hospitalization for • The use of automobile radiators containing 48 hours or longer (range: 2-18 days). Three lead-soldered parts in the illicit distillation of of these received chelation therapy; initial alcohol (i.e., "moonshine") is an important BLLs were 67, 228, and 259 ug/dL. One source of lead poisoning among persons in patient, whose BLL was 67 ug/dL, died some rural Alabama counties. during hospitalization from alcohol- withdrawal syndrome complicated by • In 1991, eight persons were diagnosed with aspiration pneumonia. elevated blood lead levels (BLLs) at a local • Patients reported moonshine ingestion hospital. ranging from 0.2 L per day to 1.5 L per day. • 9 patients had been evaluated for alcohol- • The lead contents of specimens of related medical conditions at the hospital. moonshine confiscated from two radiator- Manifestations included generalized tonic-clonic containing stills in the county in 1991 were seizures (six), microcytic anemia (five) 7400 ug/L and 9700 ug/L, compared with (hematocrit mean: 32.1%), encephalopathy nondetectable amounts (less than 1.0 ug/L) in municipal water from the county. (two), upper extremity weakness (one), and abdominal colic (one). BLLs ranged from 16 • Consumption of 0.5 L per day of moonshine containing 9700 ug/L lead would result in a ug/dL to 259 ug/dL (median: 67 ug/dL). steady state BLL of approximately 190 ug/dL. 31 32 MMWR (1992) 41(17);294-295 Principles of Environmental Toxicology Principles of Environmental Toxicology Elimination of Toxicants Kidney • Urinary. • Fecal. • Respiratory. • Other: – Saliva. – Sweat. – Milk (transfer to child). – Nails, Hair, Skin. – Cerebrospinal fluid. Hughes 33 34 Principles of Environmental Toxicology Principles of Environmental Toxicology Renal Macrostructure Renal Filtration Microstructure Renal cortex Renal medula Ureter Bovine 35 36 6
Principles of Environmental Toxicology Principles of Environmental Toxicology Renal Histology Urinary Excretion • Glomerular filtration • Tubular secretion Tubules • Tubular reabsorption Glomerulus Microscopic 37 38 Principles of Environmental Toxicology Principles of Environmental Toxicology Fecal Excretion Exhaled Air NLM • Excretion in bile to intestine. • Gas phase xenobiotics. – Active transport of toxicant parent and metabolites. • Passive diffusion from blood – Highly soluble Phase II metabolites (large, ionized) to alveolus via concentration gradient. • Excretion into the lumen of the GI tract. – The total alveolar epithelial – Direct diffusion from capillaries. Gray's Anatomy 1918 surface area within an average adult human lung has been estimated to be as large as 100-140 m2. 39 40 7