Detection and mechanisms of formation of S-(6-purinyl)glutathione and 6-mercaptopurine in rats given 6-chloropurine.
6-Chloropurine (CP) has antitumor activity against animal and human neoplasms, but the mechanism is unclear. Recently, we have shown that S-(6-purinyl)glutathione (PG), a putative metabolite of CP, is metabolized in vivo to yield the antitumor drug, 6-mercaptopurine (6-MP). In this study, CP metabolism to PG and 6-MP was investigated in an effort to provide further insights into the mechanism of CP antitumor activity. Rat hepatic and renal glutathione S-transferases metabolized CP to PG; Vmax values for liver and kidney cytosol were 166 and 24 nmol/mg of protein/min, respectively. PG was isolated and characterized by fast atom bombardment mass spectrometry from the bile of rats given CP. When rats were given CP (14 mumol/kg), PG excretion was linear with time for up to 1 hr; nearly 80% of the PG excreted at 2 hr was excreted at 1 hr. Rats given CP (10-1200 mumol/kg) excreted at 1 hr into bile nearly 18% of the dose as PG; rats given CP (400-1200 mumol/kg) excreted at 24 hr into urine nearly 4% of the dose as 6-MP and its further metabolites, 6-methylthiopurine and 6-thiouric acid. CP, PG, 6-MP, 6-methylthiopurine and 6-thiouric acid were also detected in plasma, liver and kidney of rats given CP (1200 mumol/kg); in these tissues, maximum CP concentrations were observed at 30 min, as compared to 60 to 180 min, and plasma CP concentrations were higher than those detected in liver or kidney. Liver or kidney CP metabolite concentrations at 30 to 120 min were, however, higher than those detected in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Hwang
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IY
Department of Comparative Biosciences, University of Wisconsin, Madison.
Elfarra
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AA
D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011687:Purines / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014527:Uric Acid / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism
D011506:Proteins; D011687:Purines; C079307:S-(6-purinyl)glutathione; D014527:Uric Acid; C010240:6-methylthiopurine; C010352:6-thiouric acid; D015122:Mercaptopurine; D005982:Glutathione Transferase; D005978:Glutathione; C079308:6-chloropurine