Tin-mediated heme oxygenase gene activation and cytochrome P450 arachidonate hydroxylase inhibition in spontaneously hypertensive rats

Am J Med Sci. 1994 Mar;307(3):173-81. doi: 10.1097/00000441-199403000-00003.

Abstract

The effect of SnCl2 on the transcription of the heme oxygenase gene in spontaneously hypertensive rats was examined using cDNA for the rat heme oxygenase (HO-1). An increase in renal HO-1 mRNA levels was observed in response to SnCl2 treatment. Quantitative evaluation by scanning densitometry demonstrated a maximal increase in HO-1 mRNA 24-fold over control at 8 hours after SnCl2 administration. Nuclear runoff assay using isolated renal nuclei from SnCl2-treated rats revealed an active HO-1 gene transcription. Transcription of HO-1 in rat kidney was greatly increased within 3 hours of administration of SnCl2, as evidenced by the level of [alpha 32P]UTP incorporation into nuclear RNA. As a consequence of activation of the HO-1 gene transcription, renal enzyme activity increased eightfold at 16 hours after SnCl2, and reached maximal activity of 16-fold over control at 32 hours after injection. No significant change in cytochrome P450 fatty acid omega-hydroxylase (P450 4A) mRNA was observed after SnCl2 administration. Cytochrome P450-arachidonic acid omega/omega-1 hydroxylase(s) activity (formation of 20- and 19-HETE) was significantly reduced 24 hours after SnCl2 administration and remained lower than the control level 48 and 72 hours after injection. In addition, blood pressure was reduced from 151 +/- 2.5 mm Hg to 133 +/- 2.3 mm Hg after 48 hours of SnCl2 treatment. The reduction in blood pressure preceded natriuresis. It is concluded that SnCl2 induces activation of the HO-1 gene, which is followed by elevation in enzyme activity and a decrease in cytochrome P450-arachidonic acid omega-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Blood Pressure / drug effects
  • Cytochrome P-450 CYP4A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase (Decyclizing) / metabolism
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Hypertension / metabolism*
  • Kidney / drug effects
  • Kidney / physiology
  • Male
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Tin / pharmacology*
  • Transcriptional Activation

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • Tin
  • 19-hydroxy-5,8,11,14-eicosatetraenoic acid
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • Heme Oxygenase (Decyclizing)
  • Cytochrome P-450 CYP4A