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Effect of a Suicide Substrate on the Metabolism of Steroids and Xenobiotics and on Cytochrome P-450 Apoproteins

  • T. R. Tephly
  • K. A. Black
  • M. D. Green
  • B. L. Coffman
  • G. A. Dannan
  • F. P. Guengerich
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)

Abstract

Xenobiotic administration can significantly alter forms of hepatic microsomal cytochrome P-450. Individual forms of cytochrome P-450 are known to be increased by agents, such as phenobarbital, 3-methylcholanthrene, β-naphthoflavone and pregnenolone-16α-carbonitrile1–3. Certain chemicals decrease the levels of these isoenzymes by modulating the heme biosynthetic pathway and, thereby, affect the availability of heme and the amount of hepatic cytochrome P-450, e.g. cobaltous chloride4,5. Some agents can act as suicide substrates (i.e., mechanism-based inhibitors) for one or more cytochrome P-450 forms and, thereby, promote catabolic destruction of these cytochrome P-450 species6,7. Derivatives of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) interact rapidly with cytochrome P-450, promote the rapid destruction of hepatic microsomal cytochrome P-450 and lead to the generation in vivo of N-alkyl protoporphyrins which, in turn, inhibit the activity of mitochondrial ferrochelatase, the enzyme catalyzing the last step in heme biosynthesis8–11. The result is a decreased total hepatic microsomal cytochrome P-450 level and a marked hepatic porphyria12,13.

Keywords

Hepatic Microsome Microsomal Cytochrome Methanol Poisoning Hepatic Porphyria Heme Biosynthetic Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • T. R. Tephly
    • 1
  • K. A. Black
    • 1
  • M. D. Green
    • 1
  • B. L. Coffman
    • 1
  • G. A. Dannan
    • 2
  • F. P. Guengerich
    • 2
  1. 1.The Toxicology CenterUniversity of IowaIowa CityUSA
  2. 2.Department of Biochemistry and Center in Molecular ToxicologyVanderbilt UniversityNashvilleUSA

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