Hepatic Microsomal Metabolism of Indole to Indoxyl, a Precursor of Indoxyl Sulfate

Overview

Journal Eur J Drug Metab Pharmacokinet

Date 2002 Jan 26

PMID 11808865

Citations 76

Authors

E Banoglu

G G Jha

R S King

Affiliations

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Abstract

The aim of our study was to determine which microsomal cytochrome P450 isozyme(s) were responsible for the microsomal oxidation of indole to indoxyl, an important intermediate in the information of the uremic toxin indoxyl sulfate. Indole was incubated together with an NADPH-generating system and rat liver microsomes. Formation of indigo, an auto-oxidation product of indoxyl, was used to determine the indole-3-hydroxylation activity. Apparent Km and Vmax values of 0.85 mM and 1152 pmol min(-1) mg(-1) were calculated for the formation of indoxyl from indole using rat liver microsomes. The effects of various potential inducers and inhibitors on the metabolism of indole to indoxyl by rat liver microsomes were studied to elucidate the enzymes responsible for metabolism. Studies with general and isozyme-specific P450 inhibitors demostrated that P450 enzymes and not FMO are responsible for the formation of indoxyl. In the induction studies, rate of indoxyl formation in the microsomes from untreated vs induced rats correlated nearly exactly with the CYP2E1 activity (4-nitrophenol 2-hydroxylation). These results suggests that CYP2E1 is the major isoform for the microsomal oxidation of indole to indoxyl.

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References

Gillam E, Notley L, Cai H, De Voss J, Guengerich F . Oxidation of indole by cytochrome P450 enzymes. Biochemistry. 2000; 39(45):13817-24. DOI: 10.1021/bi001229u. View

Guengerich F, Shimada T . Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem Res Toxicol. 1991; 4(4):391-407. DOI: 10.1021/tx00022a001. View

DUNNING W, CURTIS M . The role of indole in incidence of 2-acetylamino-fluorene-induced bladder cancer in rats. Proc Soc Exp Biol Med. 1958; 99(1):91-5. DOI: 10.3181/00379727-99-24258. View

Yoo J, Yang C . Enzyme specificity in the metabolic activation of N-nitrosodimethylamine to a mutagen for Chinese hamster V79 cells. Cancer Res. 1985; 45(11 Pt 1):5569-74. View

Miyazaki T, Aoyama I, Ise M, Seo H, Niwa T . An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys. Nephrol Dial Transplant. 2000; 15(11):1773-81. DOI: 10.1093/ndt/15.11.1773. View

Niwa T, Ise M, Miyazaki T . Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate. Am J Nephrol. 1994; 14(3):207-12. DOI: 10.1159/000168716. View

Koop D . Hydroxylation of p-nitrophenol by rabbit ethanol-inducible cytochrome P-450 isozyme 3a. Mol Pharmacol. 1986; 29(4):399-404. View

Perrella F . EZ-FIT: a practical curve-fitting microcomputer program for the analysis of enzyme kinetic data on IBM-PC compatible computers. Anal Biochem. 1988; 174(2):437-47. DOI: 10.1016/0003-2697(88)90042-5. View

Wong L . Cytochrome P450 monooxygenases. Curr Opin Chem Biol. 1998; 2(2):263-8. DOI: 10.1016/s1367-5931(98)80068-9. View

10.

Okey A . Enzyme induction in the cytochrome P-450 system. Pharmacol Ther. 1990; 45(2):241-98. DOI: 10.1016/0163-7258(90)90030-6. View

11.

Lawrie C, Renwick A, Sims J . The urinary excretion of bacterial amino-acid metabolites by rats fed saccharin in the diet. Food Chem Toxicol. 1985; 23(4-5):445-50. DOI: 10.1016/0278-6915(85)90138-3. View

12.

Sims J, Renwick A . The effects of saccharin on the metabolism of dietary tryptophan to indole, a known cocarcinogen for the urinary bladder of the rat. Toxicol Appl Pharmacol. 1983; 67(1):132-51. DOI: 10.1016/0041-008x(83)90252-1. View

13.

Ryan D, Ramanathan L, Iida S, Thomas P, Haniu M, Shively J . Characterization of a major form of rat hepatic microsomal cytochrome P-450 induced by isoniazid. J Biol Chem. 1985; 260(10):6385-93. View

14.

Ingelman-Sundberg M, Oscarson M, McLellan R . Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci. 1999; 20(8):342-9. DOI: 10.1016/s0165-6147(99)01363-2. View

15.

Wang T, Shankar K, Ronis M, Mehendale H . Potentiation of thioacetamide liver injury in diabetic rats is due to induced CYP2E1. J Pharmacol Exp Ther. 2000; 294(2):473-9. View

16.

Song B, Veech R, Saenger P . Cytochrome P450IIE1 is elevated in lymphocytes from poorly controlled insulin-dependent diabetics. J Clin Endocrinol Metab. 1990; 71(4):1036-40. DOI: 10.1210/jcem-71-4-1036. View

17.

Tierney D, Haas A, Koop D . Degradation of cytochrome P450 2E1: selective loss after labilization of the enzyme. Arch Biochem Biophys. 1992; 293(1):9-16. DOI: 10.1016/0003-9861(92)90358-4. View

18.

Stanfel L, GULYASSY P, Jarrard E . Determination of indoxyl sulfate in plasma of patients with renal failure by use of ion-pairing liquid chromatography. Clin Chem. 1986; 32(6):938-42. View

19.

Gonzalez F . The molecular biology of cytochrome P450s. Pharmacol Rev. 1988; 40(4):243-88. View

20.

Gillam E, Aguinaldo A, Notley L, Kim D, Mundkowski R, Volkov A . Formation of indigo by recombinant mammalian cytochrome P450. Biochem Biophys Res Commun. 1999; 265(2):469-72. DOI: 10.1006/bbrc.1999.1702. View