The interactions of hydrazine derivatives with rat-hepatic cytochrome P-450

Xenobiotica. 1984 Oct;14(10):803-14. doi: 10.3109/00498258409151479.

Abstract

The ability of different classes of hydrazine derivatives to modify cytochrome P-450 function during turnover as judged by loss of absorbance at 416 nm, loss of CO-reactive cytochrome P-450, or destruction of haem has been studied. Addition of monosubstituted hydrazines to rat-liver microsomes caused considerable loss of CO-reactive cytochrome P-450 and haem destruction; monosubstituted hydrazides caused mainly loss of CO-reactive cytochrome P-450, most likely due to abortive complex formation. Metabolism of 1,1-disubstituted hydrazines by microsomal cytochrome P-450 resulted in loss of CO-reactive cytochrome P-450 only, with no haem destruction. The 1,2-disubstituted hydrazines and hydrazides, procarbazine and iproniazid, acted similarly to the monosubstituted hydrazines, while 1,2-dimethylhydrazine elicited no response, either in observable spectral changes or loss of CO-reactive cytochrome P-450. Synthetic diazene intermediates of phenylhydrazine and N-aminopiperidine reacted rapidly with microsomal cytochrome P-450 to form a spectral intermediate resembling the putative iron porphyrin-diazenyl complex. The decomposition of certain iron porphyrin-diazenyl derivatives apparently leads to destruction of the porphyrin prosthetic group, most likely due to haem alkylation.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Heme / metabolism
  • Hydrazines / metabolism
  • Hydrazines / pharmacology*
  • Imides / metabolism
  • In Vitro Techniques
  • Microsomes, Liver / enzymology*
  • NADP / metabolism
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Porphyrins / metabolism
  • Protein Binding
  • Rats
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Hydrazines
  • Imides
  • Porphyrins
  • Heme
  • NADP
  • Cytochrome P-450 Enzyme System
  • benzphetamine N-demethylase
  • Oxidoreductases, N-Demethylating