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Nephrotoxicity induced by adenine and its analogs: relationship between structure and renal injury

T Minami1, H Nakagawa, M Nabeshima

  • 1Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan.

Biological & Pharmaceutical Bulletin
|August 1, 1994
PubMed

Insights

Twenty-four adenine analogs were tested for renal injury in mice. Compounds with strong basicity at the purine ring's 6-position, like isoguanine, caused significant kidney damage and elevated urea nitrogen (UN) and creatinine levels.

Area of Science:

  • Biochemistry
  • Toxicology
  • Nephrology

Background:

  • Adenine analogs are widely studied for their biological activities.
  • Understanding structure-activity relationships is crucial for drug development and toxicity prediction.
  • Renal injury can be a significant side effect of various chemical compounds.

Purpose of the Study:

  • To investigate the relationship between the chemical structure of adenine analogs and the induction of renal injury in a murine model.
  • To identify specific structural features of adenine analogs associated with nephrotoxicity.

Main Methods:

  • Oral administration of 24 different adenine analogs to mice.
  • Measurement of plasma urea nitrogen (UN) and creatinine levels 24 hours post-administration.
  • Histopathological examination of kidney tissues using light microscopy.
  • Time-dependent intravenous administration of selected analogs (isoguanine, adenine, 6-DMAP, 8-azaadenine) to assess acute effects.

Main Results:

  • Increased plasma UN and creatinine levels were observed in mice treated with adenine, 8-azaadenine, isoguanine, and 6-dimethyl aminopurine (6-DMAP).
  • Light microscopy revealed tubular damage, primarily in proximal tubules, in these four groups.
  • Intravenous administration of isoguanine showed a time-dependent increase in UN and creatinine.
  • A strong basicity of nitrogen at the 6-position of the purine ring was identified as a common property linked to renal injury.

Conclusions:

  • The basicity of nitrogen at the 6-position of the purine ring is a key determinant for adenine analog-induced renal injury following oral administration.
  • Isoguanine exhibits a high affinity for the kidney and demonstrates nephrotoxic potential.
  • Further research into the mechanism of toxicity for these specific analogs is warranted.

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