1

IV: Mitochondrial Function (cont’d). HEPATIC DETOXIFICATION OF a) monoamines, alcohol, toluene b) dietary or endogenous purines

(meat), heme (red meat) & bilirubin,

2

a) Detoxification of monoamines catalysed by mitochondrial outer membrane MAO

R-CHNH2

O2

H2O2

R-CH=NH

NH3

R-CHO

R-COOH-oxidation

CO2

ATP, HCO3

-

UREAurea cycle

MONOAMINE OXIDASEFlavin-containing amine oxidase

(imine)

inner membrane

outer membrane

e.g.,dopaminenorepinephrinetyraminephenethylamineoctylamineserotonin

aldehyde dehydrogenase

NAD+

NADH

3

Amine specificity for the two isoforms (A & B) in humansMAO A preferentially metabolizes serotonin.MAO B preferentially metabolizes phenethylamine, dopamine.

MAO inhibitor + dietary amines or proprietary drugs

MAOB inhibitor deprenyl (selegiline) similar to phenethylamine and increases brain dopamine levels. This is used to treat Parkinson’s disease.

But “Hypertensive crisis” is a hyperadrenergic state induced by MAO inhibitors + pressor amines (e.g., tyramine in cheese,beer,wine or soya sauce) or proprietary drugs (e.g., L-DOPA, mazindol, ephedrine, etc).

Cheese Tyramine (g/g)

English Stilton 1157

Blue 998

Mozzarella 158

Feta 76

Processed cheese slice nil

Cheese Tyramine (g/g)

Cheddar cheese, old 1530

Beer 2-11

Sherry Wine 3

Chianti Wine 25

Perry, 1996. http://www.vh.org/adult/provider/psychiatry/CPS/19.html

4

b) Detoxification of alcohols by matrix ALDH2

ETHANOL acetaldehyde

cytosolic alcoholdehydrogenase

NAD+NADHMethylpyrazole

Covalently binds to protein-NH2

NAD+

NADH

aldehydedehydrogenase

acetate ATP

CoASHacetylCoA

CO2

TCAcycle

ANTABUSE (disulfiram) or cyanamide

ADH ALDH Suscept. to alcoholism Appearance social drinking

Chromosome # 4 9, 12, 17

Caucasians 99% normal 90% normal 10% (>) --

Japanese 90% atypicial 40% deficient < 10% flushing

(ADH)

(ALDH)

CONHCH2COOH

Hippuric acid

URINE

glycine

CH3 CH2OH CHO

COOH

Toluene Benzyl alcohol Benzaldehyde

Benzoic acid

ADH

ALDH1/ALDH2

Cyt P-450

Teratogen Update: Toluene teratology. 55, 145-51, (1997)

Benzoyl-CoA synthetase

ATPCoA

Benzoyl-CoA

N-acyltransferase

c) Benzoic acidosis induced by toluene glue sniffing

ER CYTOSOL

MITOCHONDRIA

5

6

8. Hemoprotein toxicity diseases caused by heme or bilirubin

A) Rhabdomyolysis (drug induced) releases myoglobin and heme and causes kidney mitochondrial damageB) Kernicterus:- bilirubin causes neonatal brain mitochondrial damage

7

A) Myoglobin mediated rhabdomyolysis rarely caused by statins STATIN Drug BAYCOL withdrawn by BAYER, 2001

Mb Fe accumulates in kidney renal tubuleAcid lipid peroxidation (proximal tubule) mitochondrial toxicity KIDNEY Failure (7% of all cases of acute renal failure)

Muscle Cell Drug reactive metabolites Mitochondrial/cytotoxicity

CRUSH INJURYOr if LAIN IMMOBILE for hrs (e.g. EtOH, heat stroke)

Myoglobin releaseMassive muscle breakdown

a) x10 creatine phosphokinaseb) Dark brown granular casts in urine

Spontaneous myalgiasMuscle tenderness, Weakness, malaise, feverDEATH

THERAPY1.) NaHCO3 base2.) Desferoxamine

CMAJ 165(5) pg 632 (2001); J. Biol. Chem. 273, 31731-7 (1998)

Acid

8

ie. Kernicterus (brain damage caused by bilirubin in the newborn (hyperbilirubinemia))

• re-emergence (due to shorter hospital time, breastfeeding)• danger signs onset of jaundice 3 days following birth, vomiting, lethargy, poor feeding, fever, high pitched crying.• plasma bilirubin > 340 uM = exchange transfusion therapy plasma bilirubin > 240 uM = Phototherapy (blue light) Drug therapy Sn protoporphyrin (inhibits heme oxygenase).

Hemoglobin bilirubin

• Bilirubin binds to released brain mitochondrial serum albumin by competing toxicity (hearing

fatty acids or loss? brain damage drugs encephalopathy)

Heme oxygenase of reticuloendothelial cellsof spleen, liver, kidney

GlucuronylTransferase Appears at 7dafter birthGlucuronide

conjugatedbilirubin.• 0.3% mortality (yellow staining of brain)• family history, hemolytic diseases, Gilbert’s disease, diabetes (erythrocyte fragility), G6PD deficiency (Pediatrics 106, 1478-80 (2000), sickle cell.

B) Hemoglobin/heme mediated brain damage

9

Metabolic pathway of heme degradation to bilirubin and detoxification of bilirubin by glucuronidation.

NADPH O2

NADP+

H2O

NADPH: P450 Reductase

COHemeOxygenase

NADPH NADP+

Fe2+

NADPH

NADP+

NADPHBiliverdinReductase

UDP-glucuronic acidUDP

UDP-glucuronosyl transferase

(M=methyl,V=vinyl and P=propionate represent heme side chains

JAUNDICEAntioxidant, but at high concn. TOXIC TO NEONATALBRAIN MITOCHONDRIA

10

9. HEME BIOSYNTHESIS BYMITOCHONDRIA AND GENETIC

DISEASES

A) Heme biosynthesis for cytochromes, etc.B) Genetic diseases: Porphyrias and porphyrin toxicityC) Oxidative degradation of heme to bilirubin

11

A) HEME BIOSYNTHESISand porphyria diseases

12

Cytochrome Heme Synthesis - Overall picture

Heme synthesis

• Heme required for synthesis of mitochondrial cytochromes and endoplasmic reticular P450s.

• Heme required for bone marrow synthesis of hemoglobin and muscle myoglobin

• STEP 1 for heme synthesis is the synthesis of aminolevulinic acid (ALA) from succinyl CoA of the citric acid cycle and glycine

13

14

Heme biosynthesis in bone marrow (hemoglobin) and liver (cytochromes)

R.L.S. ALA synthetaseCOO

CH2

CH2

C

O

S CoA

Succinyl CoA

COO

CH2

COO

COO

CH2

CH2

C CH2

NH3

O

H+ CO2 + CoA

Feedback inhibition by heme(also induces heme oxygenase) Aminolevulinate

(ALA)

Glycine

HEME BIOSYNTHESISSTEP II

(CYTOSOL)

Fe, O2

COO

CH2

CH2

C CH

O

O

4,5-dioxovaleric acid (DOVA)

1) Brain Neuropsychiatric problems in acute porphyria, 2) Liver necrosis / cancer particularly if Fe overload

1) HEME arginate2) High carbohydrate

+

glucose-6-P NADPH

GSH reductaseGSH peroxidase

H2O2

-ketoglutaratesuccinate

citricacidcycle

CO2 + CoA

dehydrogenasecomplex

Therefore ANAPLEROTICreaction required to replacesuccinyl CoA in citric acidcycle.

ALA synthetase induced by:1) Heme deficiency due to excess P450 synthesis/induction e.g., by barbiturates Sulfonamides: Therefore an increase in urine porphyrins2) ERYTHROPOIETIN (formed by kidneys) improves quality of life of patients on kidney dialysis.3) Acute intermittent porphyria or ALA dehydratase deficiency.4) LEAD

Mitochondrial Matrix

pyridoxal

-ketoglutarateALA toxicity

Arch Biochem Biophys. 373, 368-74, (2000)

ALA SYNTHESIS AND TOXICITY

ALA accumulatesa) Acute intermittent porphyriab) Lead

NH4+, O2

ROS

DNA strand breaks

DNA ADDUCTSLIVER CANCER

Therapy

1

or leadNH2

15

Erythropoietin synthesised by kidney induces hemoglobin synthesis in bone marrow (replaces blood transfusion!)

16

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

NH HN

NH HN

COOH

COOH

COOH

COOH

HOOC

HOOC

HOOC

coproporphyrinogen I

CYP1A2

NH HN

N HN

PA

PA

A

P P

A

NH HN

NH HN

HO

COOH

COOH

COOH

COOH

HOOC

HOOC

HOOC

non-enzymatic

COOH

COOH

NH

HOOC

HOOC NH2

COOH

H2N

O

NH HN

NH HN

COOH

COOH

COOH

HOOC

HOOC

HOOC

COOH

COOHUroporphyrinogen III synthase

NH HN

NH HN

COOH

COOH

COOHCOOH

CYP1A2

LIVER/BONE MARROW cytosol

ALA

Uroporphyrin

Coproporphyrinogen III

Uroporphoryrinogen decarboxylase

-4CO2

Uroporphyrinogen I

Symmetrical

Porphobilinogen (PBG)

PBGSYNTHASE

r.l.s polymorphism

Hydroxymethylbilane

ALA DehydrataseDeficiencyPorphryia *

phosphobilinogendeaminase

Acute IntermittentPorphyria*

CongenitalErythropoieticPorphyria

PorphyriaCutaneaTarda

PorphyriaCutaneaTarda

(UROPORPHYRIA)

Cutaneous Porphyria

* Acute Porphyria

2

3

4

5

5

STEP 1

STEP 3

1

17

Heme Biosynthesis - STEP 3 - mitochondrial final steps (3 enzymes)

NH N

N HN

COOHCOOH

NH HN

NH HN

COOHCOOH

N N

N N

COOHCOOH

Fe2+

MITOCHONDRIA

O2 CO2 mitochondrialintermembrane space

Protoporphyrinogen IX

Protoporphyrinogen oxidase

i.m.

O2

Protoporphyrin IX

Ferrochelatase

i.m.r.l.s

HEME

Coproporphyrinogen oxidase

NH HN

NH HN

COOH

COOH

COOHCOOH

Coproporphyrinogen III

HereditaryCoproporphyria *

6

78

VariegatePorphyria *

Protoporphyria

Acute Porphyria

* Cutaneous Porphyria

STEP 2

Fe

18

B) PORPHYRIAS

I. Enzymes Inhibitors causing porphyriaII. Genetic porphyrias

19

I. ENZYME INHIBITORS CAUSING PORPHYRIA

PORPHYRIA - Greek “porphyros” (purple urine) an over-production disease. Often neuropsychiatric (syphilis much more so).

2) ALA dehydratase - lead

5) Uro’gen decarboxylase - PCBs, dioxin, lead, cadmium, hexachlorobenzene(fungicide - seeds). Mitochondrial oxidase - steroids (birth control pills)and estrogens

8) Ferrochelatase – lead

II. GENETIC PORPHYRIAS (Emerg Med Clin.N Am 23 (2005)885-899)

2) ALAD deficiency porphyria (Seminars in Liver Disease, 18, 95-101, 1998) excrete ALA not PBG, symptoms like (neurological).

20

Scriber et al. (eds).Metabolic and molecularbasis of inherited disease.7th ed. 1995, p.2124.

21

3) Acute intermittent porphyria (i.e. phosphobilinogenin deaminase deficiency) excrete ALA and PBG , the most common hepatic porphyria)- MEDALERT bracelet1. Symptoms - excrete PBG and ALA in the urine , high plasma PBG/ALA

- severe abdominal pain, nausea, vomiting, hypertension(cardiovascular)

then CNS - anxiety, insomnia, confusion, hallucination, paranoia then peripheral neuropathy - fatal respiratory paralysis. Liver cancer.

2. a. PBG deaminase deficiency - gene locus 11q24 (>100 mutations), autosomal dominant 1:10,000-50,000 but 1:1000 in N. Sweden (Lapland) b. Precipitated by phenytoin, phenobarbital drugs, alcohol, fasting, hormones estrogen, stress, infection or lead poisoning

3. Biochemistry of neurotoxicity a. heme deficiency P450 drug metabolism tryptophan dioxygenase brain tryptophan brain serotonin mitochondrial cytochromes (mitoch.disease) b. ALA “ROS”, mitochondrial DNA damage.4. Therapy –ALA with heme arginate (taken up by liver not b.m.), high glucose5. Mouse model (PBG knockout) - called Vincent! - behavioural studies Suspects - Van Gogh, King George III(?) (Absinthe for insomnia) 6.Diagnosis :- Patients urine exposure to sunlight (reddish brown fluorescence)

22

4) Congenital erythropoietic porphyria (Erythroid, Photosensitive)-Fe overload of b.m., uroporphyrin overload of skin and erythrocytes hemolysis

1. Symptoms: skin lesions (light) , risk of infection in early infancy Anemia (hemolysis)

Teeth reddish brown (fluorescence)2. Uroporphyrinogen III synthase deficiency

• Uroporphyrinogen I and coproporphyrin I accumulation in the skin, bone marrow, erythrocytes, urine, plasma

3. Treatment: activated charcoal (oral); b.m. transplant; gene therapy for bone marrow; blood transfusion to stop erythropoiesis in b.m.4. Only 200 diagnosed so far; werewolf, vampires (early childhood sensitiveto light skin blisters, infection disfigures) is not porphyria

23

5) Porphyria Cutanea Tarda - “heme deficiency and uroporphyrinoverload of liver” (Photosensitive; commonest porphyria;readily treated).

1. Symptoms: lesions on backs of hands and face due to photosensitization byuroporphyrin I, III or uroporphyrinogen. Abdominal pain, neural,psychiatric. ALA,porphobilinogen. 2a. Diagnosis :- urinary uroporphyrin >> coproporphyrin. b. Uroporphyrinogen decarboxylase deficiency (liver but also erythrocyte in type II): or hexachlorobenzene or dioxin induced CYP 1A2. (Turkey bread disaster). Also Fe uroporphyrinogen III synthase - uroporphyrin I.c. Candidate hemochromatosis gene leads to diagnosis of hemochromatosis

3. Precip. by alcohol, hepatitis C virus, estrogen (birth control, post-meno- pause, prostate, pregnancy), Fe. 4. Biochemistry - inactivation of decarboxylase (-SH enzyme) by “ROS” from reduced P450/P450 reductase/Fe5. Therapy:- Fe removal (phlebotomy or desferoxamine and ascorbic acid)

- chloroquine endocytosis and releases uroporphyrin chloroquine complex from hepatocytes - heme?

24

6) Hereditary Coproporphyria - coproporphyrinogen oxidase deficient, chronic fatigue syndrome. - hepatic porphyria Symptoms: liver cancer

7) Porphyria variegata - protoporphyrinogen oxidase 50% deficient. –hepatic and skin porphyria Gene locus 1q2320. 20,000 S. Africans descended from a Dutch lady in 1688 who went to S. African for marriage to another Dutch settler . Now 3/1000 S.Africans have this! Symptoms: skin and acute porphyria if exposed to sunlight,neurovisceral symptoms (abdominal pain),liver cancerDiagnosis :- plasma fluoresces when exposed to UV.Precipitated by sunlightTreatment: increase ALA synthetase by heme arginate, glucose ( NADPH) ?

25

8) Erythropoietic protoporphyria - associated with liver cancer, red urine “porphyrin and Fe overload disease” “Skin photosensitive” a. Ferrochelatase decreased 75-90% b. Symptoms: photosensitive skin (infancy),velvet knuckles, black liver c. Biochemistry - protoporphyrin IX accumulates in erythrocyte membranes and liver; intramitochondrial Fe accumulates in bone marrow - skin photo- sensitivity results from protoporphyria IX effluxing erythrocytes into plasma. d. Treatment – topical sunscreens and oral beta-carotene (ROS scav.?) e. Diagnosis –incr. protoporphyrin in erythrocytes,plasma,bile,feces I. Liver transplant; operation is difficult as operating room must be kept dark (only yellow acetate filters) II. Abdominal burns; transfused blood is destroyed as blood difficult to store.

26

C) OXIDATIVE DEGRADATION OF HEME TO BILIRUBIN

(a brain neurotoxin in babies)

27

Detoxification function of the livera) heme toxin oxidation to bilirubinb) detoxification of bilirubin by glucuronidation or albumin

phagosomeHemeoxygenase

albumin LIVER

CO

28

Degradation of heme STAGE 1Hemoglobin of old erythrocyte trappedin spleen

NH

NH

N NH

CH

CH

CH

OO

NH

NH

NH

NH

CH

CH2

CH

OO

M V M P P M M V

VMMPPMVM

BiliverdinNADPH + H+

NADP+

Biliverdin Reductase

Excreted by Reptilesand birds

HEMEO2 + NADPH

H2O + NADP+

Fe3+

BILIRUBIN(Neurotoxin to babies)

Bone marrow

transferrin

Plasma Serum Albumin Complex LIVER

Modified fromFig. 28-31 Stryer4th Ed.

NEONATAL JAUNDICEBilirubin accumulates in newborns.(destroy with sunlight).

Heme oxygenase (ER)

CO

H2O soluble

exhaled

ANTIOXIDANT

Fat soluble

29

STAGE II - ligandin in hepatocyte surface membrane traps bilirubinfrom plasma and helps transport it into the liver where it is glucuronidated

Albumin- bilirubin

(a GSH transferase)

30

*mutated gene in Gaucher’s disease(carried by 15% ofpopulation)

NH

NH

NH

NH

CH

CH2

CH

OO

VMMMVM

COOCOO

OH

OH

H

UDP

H

OHH

OH

COO

UDP-glucuronate

+

Bilirubin

Endoplasmic reticulumUDP-glucuronosyltransferase (UGT 1A1*)

NH

NH

NH

NH

CH

CH2

CH

OO

VMMMVM

COOC

OH

OH

H

O

H

OHH

OH

COO

O

BILIRUBIN DIGLUCURONIDE (Soluble bilirubin diglucuronide secreted

into the bile)

BILIRUBIN MONOGLUCURONIDE

UDP

UDP gluc. + UGT 1A1

31

10. a) N-Catabolism of Amino Acids (The Urea Cycle) and the Detoxification of Ammonia (very toxic)

Mitochondrial Function (Con’t).

b) N-Catabolism of Purines• reperfusion injury and drug therapy• Genetic diseases: HGPRT• Gout, Lesch-Nyhan syndrome

32

Disposal of nitrogen by mitochondria a) The urea cycle: Detoxification of NH3

ALANINE

Alanineaminotransferase

Pyruvate

-ketoglutarate

glutamate

aspartateaminotransferase

aspartate

oxaloacetate

citrulline +

arginine +fumarate

fumarase

malatemalate

dehydrogenase

UREA

phospho-enol-pyruvate

INNER MITOCHONDRIAL MEMBRANE transporter

Pi

Cytosol

MitochondrialMatrix

Pyruvate

Alanine

malate

NAD+

glutamatedehydrogenase

NADH

citrulline

NH3

ornithinetranscarbamoylase

2 ATP

+ HCO3- carbamoyl phosphate

synthetase

H+

-ketoglutarate

glutamate

oxaloacetate

arginosuccinatesynthetase argininosuccinase

H2Oarginase

ornithine

ornithine

carbamoylphosphate

transporter

Alanineaminotransferase

CO2

(note: urea cycle enzyme in blue)

33

Formation of urea from amino acids

Glutamate -ketoglutarate

Mitochondrial Function (Con’t).

transaminase

dehydrogenase

Urea cycle

dehydrogenase-amino acid -ketoglutarate NADH + NH3

+

NAD++ H2OGlutamate-Keto acid

H2N C NH2

O

UREA

+ NAD(P)+ H2O+ NH4+

+ + NAD(P)HH3N CH

COO

CH2

CH2

COO

O CH

COO

CH2

CH2

COO

34

IV: Peroxisomes Function• β-oxidation of fatty acids but oxidase forms H2O2

• Glyceraldehyde is metabolised to D-glycerate and glucose via glycolate (glycolate oxidase forms H2O2 and glyoxylate)

• Catalase detoxifies H2O2 to form oxygen and H2O and cooxidises other substrates, including phenols, formic acid, formaldehyde, and methanol.

• Glyoxylate detoxified by peroxisomal alanine:glyoxylate transaminase to form glycine & pyruvate. Otherwise glyoxylate would be oxidised by lactate dehydrogenase to oxalic acid which causes oxalate stone formation & kidney damage.

• Biosynthesis of bile acids and ether phospholipids

35

V: CYTOSOLIC FRACTION

N-catabolism of purines

Glycogen synthesis and glycogenolysis

36

Disposal of nitrogen (Con’t): b) N-catabolism of purines in the cytosol & peroxisomes

HG

PR

T +

PR

PP

HG

PR

T +

PR

PP

Voet pg. 714.

37

1) N-catabolism of purines can be lethal Reperfusion Injury

e.g. Myocardial infarction or Paraplegia

a) ISCHEMIC STAGE

• Lack of O2no ATP synthesis by heart muscle mitochondria. ADPAMPhypoxanthine accumulates and leaves muscle cell to enter endothelial cell.• Acidosis causes endothelial cell xanthine dehydrogenasexanthine oxidase• Acidosis results from marked increase in glycolysis to form ATP + lactic acid (to keep cells alive by maintaining ATP levels)

b) Reperfusion of O2

• O2 is the substrate for xanthine oxidase

•Damaged endothelial and muscle cells (ischemic toxicity) release factors which recruit neutrophils (inflammatory reaction activated NADPH oxidaseO2*-.

Accumulated xanthine and hypoxanthine O2 (Endothelial cell)

Cytosolic Fraction

Xanthineoxidase

38

Drugs which prevent reperfusion injury

1) Allopurinol – inhibitor of xanthine oxidase2) Desferal – Complexes Fe2+

3) Antioxidants e.g. Lazeroids (upjohn) to prevent membrane lipid peroxidation4) Removal of H2O2 by NADPH (e.g. glucose) or GSH (e.g. methionine) or dietary Se.

H2O2 OH

H2O

GSSG + H2O

GSH Peroxidase

Catalase (activated by NADPH)

2 GSH

5) Anti-inflammatory drugs (e.g. indomethacin or phenylbutazone)6) Ca2+ Blockers

39

Treatment or to prevent Ischemic damage (reperfusion injury)

HC

NC

C

CN

HN

CH

N

OH

HC

NC

C

CN

HC

N

N

OH

HYPOXANTHINE ALLOPURINOL

Xanthine Oxidase

C

NC

C

CN

HC

N

N

OH

HO

ALLOXANTHINE (oxypurinol)

The synthesis of urate from hypoxanthine and xanthine oxidase decreases soon after the administration of allopurinol.

40

Figure 22.22 (Voet) – By James Gilroy• Defects in excretion of uric acid and/or partial deficiency in HGPRT activity due to mutation in HGPRT gene• Uric acid precipitation in joints – crystals activate leukocytes H2O2 and O2

*- arthritis.

• Adults (0.55%) in males• Often suffered by over-achieving males with too much drive and ambition (e.g. pharmacists).

2) Purine catabolism can be painful and cause joint damage

Drugs which trigger gout• Anticancer drug treatment of acute leukemia resulting in destruction of nucleic acids and accumulation of uric acid.• Long term diuretic treatment (impair glomerular filtration)Risk Factors• Eating too much meat (purines e.g. xanthine)• Alcohol ingestion increases hypoxanthine • age, male gender, high body mass index, hypertension.

41

Hypoxanthine + PRPP PPi + IMP Guanine + PRPP PPi + GMP

3) Genetic Deficiency of HGPRT LESCH-NYHAN SYNDROME – X-linked recessive (X-chromosome gene) 50% of cells have a complete deficiency of salvage enzyme HGPRT (Hypoxanthine – guanine phosphoribosyl transferase) or lyase (ASLI) which catalyses:

Cytosolic Fraction

XMP

adenylsuccinate

AMP

Lyase(ASLI)

synthetase

Nucleotidesynthesis

adenosine

PRPP (5-phosphoribosyl-a-pyrophosphate)

Results in enormous overproduction of PRPP,hypoxanthine,uric acid.

Ribose-5-phosphate

ATP ADP

Pyrophosphokinase

O

OHOH

HH

H

OH

CH2OP3O2

P O P O

O

O

O

O

HGPRT

42

Children • Neurological dysfunctions ( serotonin metabolism)• Aggressive or self mutilating but affectionate, quick to laugh, likeable and open.• Tend to chew their lips and finger tips• Mental retardation• Cerebral palsy and spasticity• Obscene gestures• Flinging their feces• Die before reaching the age of 10 due to renal failure.• If mild enough, gout will develop into adulthood.

Children with LESCH-NYHAN SYNDROME(Incidence 1:380,000) (HGRPT deficiency)

43

DRUG THERAPY

ALLOPURINOL is the most useful drug for treatment of GOUT.

Inhibition of uric acid production because xanthine oxidase (terminal step to uric acid production) is inactivated by allopurinol.

However, neurological problems associated with LESCH-NYHAN SYNDROME which have been attributed to PRPP and de novo purine synthesis can not be alleviated by allopurinol. Allopurinol will prevent uric acid stones accumulating in the kidney and will prevent kidney infections and hematuria.

NEUROLOGICAL TOXIC MECHANISM UNKNOWN HGPRT, which is required for purine synthesis is still functionally deficient andPRPP accumulates.Dopamine neuron function is still lost and neurological problems persist.

The End

• Don’t memorize 9, 21, 31, 33, 35, 37, 43

44