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BIOTRANSFORMATION, Drug metabolism,
detoxification
Phase 2 conjugation
susulfation Glucuronidation (80%)Conjugation with amino acidsglycosylation
acetylation
GSH conjugation12%
phase I phase II
nucleophilicmetabolites
glucuronidessulfate esters
electrophilicmetabolites
GSH conjugates
X
DNA, RNA, protein
Ways of conjugation
• Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases
Conjugation ofsalicylic acid
Enzyme and transporter in the ER membrane
Role of UGT-s in activation of drugs
morphinsteroids
bile acids
retinoids
policyclic aromatic hydrocarbons
heterocyclic aromatic amines
Crigler Najjar syndr.
bilirubin encephalopathia, fatal
Hyperbilirubinemias
unconjugated hyperbilirubinemias
Gilbert disease
Low UGT activity
treatment: inducer phenobarbital
benign, 5-6 % of population
Hyperbilirubinemias
Conjugated hyperbilirubinemias
Transport of conjugates is disturbed
Dubin Johnson syndr.
Rotor syndr.
Expression of MRP2 is depressed
Ways of conjugation
• Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases
• Sulfation – PAPS - sulfotransferases
Sulfate conjugation of coumarine
Ways of conjugation
• Glucuronidation – UDP glucuronate – UDP-glucuronosyl transferases
• Sulfation – PAPS – sulfotransferases
• GSH conjugation - GSH, acetyl CoA - GSH transferases
Biotransformation ofacetaminophen
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
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
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
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
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
Toxicity 1.
dosis
5-10 different drugs/patient
Logarythmic increase of adverse drug effects with the number of drugs
nutrition
alkoholism
Intracellular cofactors
NADPHUDPGAPAPSGSHvitamines
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
Toxicity 3.
Genetic differencesTreatment of populations
INH (isoniazid) N acetyl transferase
Pathological circumstances
ageing
Gender differences
diabetes mellitusLiver diseases
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
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