Related Experiment Videos
Renal transport of 2'-deoxytubercidin in mice
Abstract:
Previous results [J. F. Kuttesch, Jr. and J. A. Nelson, Cancer Chemother, Pharmac. 8, 221 (1982)] from this laboratory indicate that mechanisms exist for renal secretion of 2'-deoxyadenosine and possibly for reabsorption of adenosine in humans and in mice. Since significant metabolism of these purine nucleosides occurs even in the presence of adenosine deaminase inhibitors, the renal handling of a compound which is not significantly metabolized by the deaminase or by kinases was studied. Unlike 2'-deoxyadenosine itself, the 2'-deoxyadenosine analog, [4-amino-7-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrrolo-(2,3-d)pyrimidine; 2'-deoxytubercidin], is not significantly metabolized by mammalian tissues. In mice, the renal plasma clearance of 2'-deoxytubercidin exceeded that of inulin by about 3-fold. Also, mouse kidney slices concentratively accumulated 2'-deoxytubercidin by a saturable and metabolically dependent process. The uptake by mouse kidney slices was inhibited by classical substrates for the organic cation secretory system (tetraethylammonium, choline and N1-methylnicotinamide) but was not markedly inhibited by classical substrates for the organic anion secretory system (p-aminohippurate, phenol red and probenecid). Since 2'-deoxytubercidin inhibited the active, concentrative uptake of [14C]tetraethylammonium, but failed to inhibit the uptake of p-[14C]aminohippurate by mouse kidney slices, it is concluded that 2'-deoxytubercidin may be secreted by the organic cation system. Additional studies are required, however, to unequivocally establish the relationships between 2'-deoxytubercidin, 2'-deoxyadenosine and tetraethylammonium renal secretory mechanisms.
Insights
This study investigated the renal handling of 2'-deoxytubercidin, a non-metabolized nucleoside analog. Results suggest 2'-deoxytubercidin is actively secreted by the kidney via the organic cation transport system.
Area of Science:
- Pharmacology
- Nephrology
- Biochemistry
Background:
- Previous research indicated renal secretion of 2 -deoxyadenosine and potential reabsorption of adenosine.
- Significant metabolism of purine nucleosides occurs, necessitating study of non-metabolized compounds.
- 2 -deoxytubercidin, a 2 -deoxyadenosine analog, is not significantly metabolized by mammalian tissues.
Purpose of the Study:
- To investigate the renal handling of 2 -deoxytubercidin, a non-metabolized purine nucleoside analog.
- To determine if 2 -deoxytubercidin is handled by specific renal transport systems.
- To elucidate the mechanisms of renal secretion and reabsorption for nucleoside analogs.
Main Methods:
- Measuring renal plasma clearance of 2 -deoxytubercidin in mice relative to inulin.
- Assessing concentrative uptake of 2 -deoxytubercidin by isolated mouse kidney slices.
- Investigating the effect of organic cation and anion transport substrates on 2 -deoxytubercidin uptake.
- Examining the inhibitory effects of 2 -deoxytubercidin on the uptake of known substrates for organic cation and anion transporters.
Main Results:
- Renal plasma clearance of 2 -deoxytubercidin was approximately 3-fold higher than that of inulin in mice.
- Mouse kidney slices demonstrated saturable, metabolically dependent, and concentrative accumulation of 2 -deoxytubercidin.
- Uptake of 2 -deoxytubercidin was inhibited by organic cation substrates (e.g., tetraethylammonium) but not by organic anion substrates (e.g., p-aminohippurate).
- 2 -deoxytubercidin inhibited the uptake of [14C]tetraethylammonium but not p-[14C]aminohippurate, suggesting interaction with the organic cation system.
Conclusions:
- 2 -deoxytubercidin is actively secreted by the mouse kidney.
- The organic cation secretory system is likely involved in the renal transport of 2 -deoxytubercidin.
- Further research is needed to confirm the relationship between 2 -deoxytubercidin, 2 -deoxyadenosine, and tetraethylammonium renal secretory mechanisms.