Effects of aldose reductase inhibitors, AL-4114 and AL-1576, on hepatic biotransformation in rabbit and rat

J. C. Veltman, A. Kumar, R. A. Sanders, J. B. Watkins

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations

Abstract

Aldose reductase is part of the sorbitol pathway, which has been linked to many diabetic complications such as retinopathy and cataracts. This study has determined whether two aldose reductase inhibitors, AL-1576 and AL-4114, may be inducers of hepatic biotransformation in New Zealand white rabbits or Sprague-Dawley rats. The drugs were administered either by intraperitoneal injection (ip) once a day for 4 days (10 mg/kg or 50 mg/kg) to rats and rabbits or by topical-ocular dosing three times a day for 14 days to rabbits (0.5% or 5.0%). Rats dosed ip had increased hepatic cytochrome P450 monooxygenase activity toward methoxycoumarin and benzphetamine, glutathione S-transferase activity toward 1-chloro 2,4-dinitrobenzene, and uridine diphosphate (UDP)-glucuronosyltransferase activity toward 4-hydroxybiphenyl and 1-naphthol. In rabbits, ip dosing increased only glucuronosyltransferase activity toward 4-hydroxybiphenyl after AL-4114, and no hepatic biotransformation enzyme activities were increased after topical-ocular dosing with either AL-4114 or AL-1576. Activities of other enzymes, including P450 monooxygenase toward benzo(a)pyrene, N-acetyltransferase toward 2- aminofluorene and β-naphthylamine, UDP glucuronosyltransferase toward 4- methylumbelliferone, styrene oxide hydrolase, and 2-naphthol sulfotransferase, were not increased by either topical-ocular or ip dosing with AL-1576 or AL-4114 in either rats or rabbits, although ip dosing with AL-1576 decreased monooxygenase activity toward ethoxyresorufin in rabbit liver. These results indicate that AL-1576 and AL-4114, though inducers of hepatic biotransformation in rats, do not induce hepatic biotransformation in rabbits when administered by either ip or topical ocular dosing.

Original languageEnglish (US)
Pages (from-to)603-617
Number of pages15
JournalInternational Journal of Toxicology
Volume17
Issue number6
DOIs
StatePublished - Nov 1998

Keywords

  • Aldose reductase inhibitors
  • Biotransformation
  • Cytochrome P450 monooxygenase
  • Glucuronosyltransferase
  • Liver
  • Rabbit
  • Rat

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Health, Toxicology and Mutagenesis

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