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)


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.


Hepatic Microsome Microsomal Cytochrome Methanol Poisoning Hepatic Porphyria Heme Biosynthetic Pathway 
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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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