Nephrotoxicity Induced by Adenine and Its Analogs: Relationship between Structure and Renal Injury.

Abstract

Twenty-four adenine analogs were administered to mice and the relationship between the structure of analogs and the occurrence of renal injury was examined. Plasma urea nitrogen (UN) and creatinine levels were measured 24 h after oral administration of analogs. Both levels increased in the adenine-, 8-azaadenine-, isoguanine-, or 6-dimethyl aminopurine (6-DMAP)-administered group, but did not increase in the other analog groups. From light microscopy, the damages of tubuli, mainly of proximal tubuli, were observed in the kidneys of these four groups. The common property of these compounds is the strong basicity of nitrogen which binds the 6-position of the purine ring. Furthermore, UN and creatinine increased time-dependently with intravenous administration of isoguanine. When adenine was intravenously administered, UN slightly increased at 1 h, but creatinine was unchanged. No changes were observed in the 6-DMAP- or 8-azaadenine-administered group. The basicity of nitrogen which binds to the 6-position of the purine ring is thus considered to be related to the occurrence of renal injury with oral administration, and isoguanine has high affinity with the kidney.

Evaluation of biomarkers of kidney injury following 4% succinylated gelatin and 6% hydroxyethyl starch 130/0.4 administration in a canine hemorrhagic shock model

“…Another unexpected finding in our study was the increase observed in uNGAL, uKIM, and uCLUST in the FWB group, compared with the CRYST group. This may be explained by prolonged hypoperfusion, as indicated by higher venous‐arterial carbon dioxide difference at T20, or nephrotoxicity of either filtered free hemoglobin, which was not quantified, or the anticoagulant solution …”

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

“…For example, ddA ( 447 ) undergoes acid-catalyzed degradation with a rate constant that is 42,000 times faster than adenosine ( 444 ), which can be attributed to the removal of the inductive electron-withdrawing effect of the 2,3-hydroxyl substituents which would destabilize the oxocarbonium intermediate . Degradation of ddA ( 447 ) upon exposure to gastric acid following oral administration gave adenine ( 453 ), which is further metabolized to give 2,8-dihydroxyadenine ( 454 ), which concentrates in renal tubules where it crystallizes causing nephrotoxicity . ddA ( 447 ) also undergoes cellular deamination to ddI ( 452 ) which is converted via 456 to ddA-5′-triphosphate ( 457 ), the active metabolite responsible for inhibiting HIV-1 reverse transcriptase (Scheme ).…”