Role of metabolism in Drug-Induced Liver Injury (DILI) Drug Metab Rev. 2007;39(1):

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1 Role of metabolism in Drug-Induced Liver Injury (DILI) Drug Metab Rev. 2007;39(1):

2 Drug Metab Rev. 2007;39(1):

3 Drug Metab Rev. 2007;39(1):

4 A schematic representation of the most relevant transporters in the human hepatocyte 1) the solute carrier (SLC) family Na+-taurocholate co-transporting polypep-tides (NTCP), organic anion-transporting polypeptides (OATPs), organic anion transport-ers (OATs), organic cation transporters (OCTs); and 2) the ATP-binding cassette (ABC) transporter family multi drug resistance proteins (MDR), bile salt exportpump (BSEP) (both belong to the ABCB family), breast cancer resistance protein (BCRP; belonging to the ABCG or White family) and multi drug resistance associated proteins (MRP s), belonging to the ABCC family Drug Metab Rev. 2007;39(1):

5 Pharm Res (5):719-35

6 Pharm Res (5):719-35

7 Nuclear receptor-mediated regulation of a complex network of genes involved in transport of drugs and bile acids Methods Enzymol. 2005;400: Pharm Res (5):719-35

8 Enterohepatic circulation of bile acids Pharm Res (10):

9 Pharm Res (10): Bile acid-induced regulation of hepatic and intestinal bile acid transporters

10

11 Glutathione and Sulfo- or S-Transferases Reactions of GSH One of the cellular systems which constitutes a protective function against toxicants centers around glutathione.

12 Properties which contribute to this protective role: (a) SH is a very reactive nucleophilic site (b) tissue concn generally is relatively high the normal concn of GSH in liver of various animals is 4-10 mm (c) multiple forms of glutathione S-transferases which catalyze the reaction of various electrophilic compounds with GSH, thereby neutralizing their electrophilic sites and rendering the products more water-soluble in a (generally) overall detoxication process. 8 transferases can be chromatographically separated from rat liver. Substrates of S-transferases: Although each of the S-transferases has some preference for certain substrates, each of the transferases often have overlapping substrate specificities and not rigid specificities. (d) GSH can non-enzymatically reduce a number of substances, such as peroxides and free radicals and a later example of carbonyl compounds with reactive double bonds

13 At least 2 separate cellular GSH pools: Cytosol Mitochondria

14

15 Further Metabolism of GSH Conjugates Typical pattern for further metabolism: Acetylation of free NH2 of cysteinyl residue yields a mercapturic acid [S-alkylated derivative of N-acetylcysteine] Treatment of animal with toxicant = excretion of the metabolite as a mercapturic acid

16 In contrast to the amides formed by conjugation of xenobiotics to other amino acids, glutathione conjugates are thioethers, which form by nucleophilic attack of glutathione thiolate anion (GS-) Glutathione S transferases are present in most tissues, with very high concentrations in liver. Conjugation reactions can be divided into two types: (Michael) addition reactions = glutathione is added to an activated double bond or strained ring system Displacement reactions = glutathione displaces an electron withdrawing group (esp. halides)

17 Cellular Distribution Cytosolic (>95% of total) Glutathione S-transferases: 7 classes (with multiple subunits within each class) alpha (i.e., GSTA). Humans 4 subunits, rats at least 5 subunits mu GSTM. Humans 6 subunits, rats 6 subunits pi GSTP Theta Kappa Sigma Zeta Microsomal (<5% of total): distinct from cytosolic transferases

18

19 diethyl fumarate

20

21 2 5

22 (b.2) Decrease tissue GSH concn. by inhibition of GSH synthesis glutamate + cysteine yield glutamylcysteine (catalyzed by gamma-glutamylcysteine synthetase) Inhibitor: BSO=Buthionine sulfoximine (also by Methionine sulfoximine) Glutathione biosynthesis γ- glutamylcysteine synthetase (glutamate cysteine ligase) glutathione synthetase web.indstate.edu/thcme/mwking/glutathione.gif

23 Inhibitors of glutathione biosynthesis

24

25 L-2-oxothiazolidine-4-carboxylate ( 2-oxo ) 2-Oxo readily enters cells and is converted intracellularly to cysteine

26 Effects of Altered GSH Concn on Hepatic Toxicity: Gillette and coworkers Two examples have been extensively studied: Acetaminophen Bromobenzene (metabolized via arene oxide intermediate) Both compounds exert their cellular toxicity liver by conversion by the cytochrome P.450 dependent mixed function oxidase to different reactive metabolites which then react covalently with tissue macromolecules.

27

28 For the same toxicant namely acetaminophen what effect does the tissue concn of GSH have on the extent of covalent reaction of the metabolite to hepatic proteins. Two types of experiments: (measurements at 120 min. after acetaminophen dosage in mice) *Threshold normal cell has excess GSH

29 1 hour after administration of single dosage level (750 mg/kg mice) of acetaminophen At any dosage, 2-15% of acetaminophen administered to animals is transformed by the cytochrome P-450 dependent MFO to a chemically reactive metabolite. At low or therapeutic dosages, virtually all of the reactive metabolite is converted to a glutathione conjugate that is ultimately excreted as a mercapturic acid derivative. But at high dosages of the drug, the GSH in liver is decreased to such an extent that the reactive metabolite can no longer be completely inactivated by GSH and a portion of the metabolite becomes covalently bound to liver proteins.

30 25% 15% 31% 22% 47% 39% James et al. Toxicol Appl Pharmacol Feb;118(2):159-68

31 Control 34±4 James et al. Toxicol Appl Pharmacol Feb;118(2):159-68

Polar bodies are either introduced or unmasked, which results in more polar metabolites Phase I reactions can lead either to activation or

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