Thiopurine methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs such as 6-mercaptopurine and 6-thioguanine. TPMT activity in the kidney of adult male Sprague-Dawley rats was more than twice that in the kidneys of age-matched female animals, 329 ± 22 U/g of tissue vs. 147 ± 15 U/g (mean ± S.E.M., N = 5). There was no significant male-female difference in splenic TPMT activities (70 ± 6 for males vs. 77 ± 3 U/g of tissue for females). Renal TPMT in male rats was reduced to 100 ± 4 U/g of tissue 2 1/2 weeks after hypophysectomy and was reduced to 197 ± 11 U/g of tissue 7 days after orchiectomy. Both procedures resulted in striking decreases in circulating levels of testosterone. Neither hypophysectomy nor ovariectomy altered renal TPMT activity in female rats, and neither hypophysectomy nor sex organ ablation altered splenic TPMT activity in either sex. Eight days after injection with testosterone enanthate, 200 mg/kg s.c., renal TPMT activity increased 80% in sham-operated male rats, 212% in castrated male rats and 160% in normal female rats. The increase in renal TPMT activity in response to testosterone enanthate was blocked by treatment with the protein synthesis inhibitor cycloheximide. The results of experiments in which partially purified human kidney TPMT activity was added to renal homogenates from testosterone treated and untreated animals made it unlikely that the increases in enzyme activity in response to testosterone were due to changes in TPMT activators, inhibitors or competing enzyme systems. The results of this series of experiments were compatible with the conclusion that the activity of TPMT in the rat kidney is regulated by testosterone.
|Original language||English (US)|
|Number of pages||5|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1981|
ASJC Scopus subject areas
- Molecular Medicine