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BIOTRANSFORMATION, Drug metabolism,
detoxification
Phase 2 conjugation
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susulfation Glucuronidation (80%)Conjugation with amino acidsglycosylation
acetylation
GSH conjugation12%
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phase I phase II
nucleophilicmetabolites
glucuronidessulfate esters
electrophilicmetabolites
GSH conjugates
X
DNA, RNA, protein
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Ways of conjugation
• Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases
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Conjugation ofsalicylic acid
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Enzyme and transporter in the ER membrane
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Role of UGT-s in activation of drugs
morphinsteroids
bile acids
retinoids
policyclic aromatic hydrocarbons
heterocyclic aromatic amines
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Crigler Najjar syndr.
bilirubin encephalopathia, fatal
Hyperbilirubinemias
unconjugated hyperbilirubinemias
Gilbert disease
Low UGT activity
treatment: inducer phenobarbital
benign, 5-6 % of population
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Hyperbilirubinemias
Conjugated hyperbilirubinemias
Transport of conjugates is disturbed
Dubin Johnson syndr.
Rotor syndr.
Expression of MRP2 is depressed
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Ways of conjugation
• Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases
• Sulfation – PAPS - sulfotransferases
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Sulfate conjugation of coumarine
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Ways of conjugation
• Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases
• Sulfation – PAPS – sulfotransferases
• GSH conjugation - GSH, acetyl CoA - GSH transferases
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Biotransformation ofacetaminophen
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Ways of conjugation
• Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases
• Sulfation – PAPS – sulfotransferases
• GSH conjugation - GSH, acetyl CoA - GSH transferases
• Acetylation – acetyl CoA
• Amino acid conjugation – amino acids
• Methylation - SAM
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Phisiological substrates: steroidsEicosanoidsFatty acidslipidshydroperoxidesretinoidsaceton
(inducers ?)
Xenogenic substrates(inducers ?)
Ah receptor: aromatic hydrocarbon receptor
intracellular receptors: CAR, PXR, VDR, FXR, RXR, HNF4
Overlapping substrate, inducer specificity
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Biotranszformation reactions in intermediery metabolism
Bile acid
steroid hormones
synthesisconjugation
synthesisconjugation
„Maturation” of D vitamin
prostaglandin, leukotriene synthesisconjugation
Synthesis of cholesterin
chatecholamines synthesisconjugation
bilirubin „synthesis”conjugation
Synthesis of (poly)unsaturated fatty acids
Oxidation of aceton
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androstane-dion estron
P450aromatase
estron
sulfo-transferase
estron- sulphate
estronEstron-sulphate
szteroidszulfatáz
1. phase:ligand activation by oxygenation
2. phase:ligand inactivation by conjugation
ligand reactivation by deconjugationl
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Consequences of Biotransformation
actíve inactive drogs, hormones (steroid, prostanoid)
inactive active drogs (imipramine)hormones (testosterone)vitamin (D vitamin)chemical carcinogenesis (nitrosamines)
biosynthesis aceton glucose Synthesis of leukotrienes
inactivation, „detoxification”
toxicity
Role of induction in regulation
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Toxicity 1.
dosis
5-10 different drugs/patient
Logarythmic increase of adverse drug effects with the number of drugs
nutrition
alkoholism
Intracellular cofactors
NADPHUDPGAPAPSGSHvitamines
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Toxicity 2.
Aspecific enzyme systems
Addition of various drugs
Competition of substrates
Changes in induction e.g. Coumarine
Biotransformation enzymes in livers of newbornsTreatment of mothers at delivery
chloramphenicolmorfin
gray baby szindróma
Hyperbilirubinaemia of newborns low UGT
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Toxicity 3.
Genetic differencesTreatment of populations
INH (isoniazid) N acetyl transferase
Pathological circumstances
ageing
Gender differences
diabetes mellitusLiver diseases
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ethanol
acetaldehid
acetate
CYP2E1ADHalcohol dehydrogenase
catalase
KM:0,2-2 mM
KM:8-10 mM
aldehyde dehydrogenase
cytosol SER peroxisome
mitokondrium
NAD
NADH
H2O2
H2O
NAD
NADH
NADPH
NADP
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ethanol
acetaldehid
acetate
CYP2E1ADHalcohol dehydrogenase
catalase
KM:0,2-2 mM
KM:8-10 mM
aldehyde dehydrogenase
cytosol SER peroxisome
mitokondrium
NAD
NADH
H2O2
H2O
NAD
NADH
NADPH
NADP
↓Fatty liver
→ stimulated metabolism of other drugs
→ acetaldehyde toxicity autoimmune pathology