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