Induction of hepatic cytochrome P-450 by natural steroids

Relationship to the induction of δ-aminolevulinate synthase and porphyrin accumulation in the avian embryo

Karl Anderson, Umberto Freddara, Attallah Kappas

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Certain steroid hormones and their metabolites are potent inducers of δ-aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in the liver. In this study we examined the influences of a number of natural steroids on the induction of liver cytochrome P-450, δ-aminolevulinate synthase, and protoporphyrin in the chick embryo in ovo, and the effects of "priming" with a small dose of 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC), an inhibitor of ferrochelatase. There was a close relationship between the induction of cytochrome P-450 and δ-aminolevulinate synthase by steroids in experiments with, as well as in experiments without, DDC priming. In most instances, 5β steroids were more potent inducers than were the corresponding 5α epimers: 5β steroids more potently induced δ-aminolevulinate synthase and/or porphyrin accumulation for 11 of 15 steroid pairs tested and cytochrome P-450 for 10 of 14 pairs. With DDC priming, steroid induction of δ-aminolevulinate synthase and protoporphyrin was greatly accentuated, while the increase in cytochrome P-450 was partially prevented. This experimental model, is reminiscent of certain human porphyrias in which clinical expression is probably due in part to interactions of endogenous steroids with genetic deficiencies of heme pathway enzymes, and in which there is in the liver enhanced activity of δ-aminolevulinate synthase and accumulation of heme pathway intermediates, while hepatic cytochrome P-450 content is largely maintained. These features suggest that decreases in the regulatory "free" heme pool(s) in the liver can occur and produce pronounced δ-aminolevulinate synthase induction without the development of a marked deficiency of the major liver hemoprotein, cytochrome P-450.

Original languageEnglish (US)
Pages (from-to)597-608
Number of pages12
JournalArchives of Biochemistry and Biophysics
Volume217
Issue number2
DOIs
StatePublished - 1982
Externally publishedYes

Fingerprint

Porphyrins
Cytochrome P-450 Enzyme System
Embryonic Structures
Steroids
Liver
Heme
Dicarbethoxydihydrocollidine
Steroid hormones
Ferrochelatase
Porphyrias
Biosynthesis
Enzymes
Metabolites
Chick Embryo
Experiments
Theoretical Models
Hormones

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

@article{67e8753007fa4f3a892eb27467fe32b6,
title = "Induction of hepatic cytochrome P-450 by natural steroids: Relationship to the induction of δ-aminolevulinate synthase and porphyrin accumulation in the avian embryo",
abstract = "Certain steroid hormones and their metabolites are potent inducers of δ-aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in the liver. In this study we examined the influences of a number of natural steroids on the induction of liver cytochrome P-450, δ-aminolevulinate synthase, and protoporphyrin in the chick embryo in ovo, and the effects of {"}priming{"} with a small dose of 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC), an inhibitor of ferrochelatase. There was a close relationship between the induction of cytochrome P-450 and δ-aminolevulinate synthase by steroids in experiments with, as well as in experiments without, DDC priming. In most instances, 5β steroids were more potent inducers than were the corresponding 5α epimers: 5β steroids more potently induced δ-aminolevulinate synthase and/or porphyrin accumulation for 11 of 15 steroid pairs tested and cytochrome P-450 for 10 of 14 pairs. With DDC priming, steroid induction of δ-aminolevulinate synthase and protoporphyrin was greatly accentuated, while the increase in cytochrome P-450 was partially prevented. This experimental model, is reminiscent of certain human porphyrias in which clinical expression is probably due in part to interactions of endogenous steroids with genetic deficiencies of heme pathway enzymes, and in which there is in the liver enhanced activity of δ-aminolevulinate synthase and accumulation of heme pathway intermediates, while hepatic cytochrome P-450 content is largely maintained. These features suggest that decreases in the regulatory {"}free{"} heme pool(s) in the liver can occur and produce pronounced δ-aminolevulinate synthase induction without the development of a marked deficiency of the major liver hemoprotein, cytochrome P-450.",
author = "Karl Anderson and Umberto Freddara and Attallah Kappas",
year = "1982",
doi = "10.1016/0003-9861(82)90542-2",
language = "English (US)",
volume = "217",
pages = "597--608",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Induction of hepatic cytochrome P-450 by natural steroids

T2 - Relationship to the induction of δ-aminolevulinate synthase and porphyrin accumulation in the avian embryo

AU - Anderson, Karl

AU - Freddara, Umberto

AU - Kappas, Attallah

PY - 1982

Y1 - 1982

N2 - Certain steroid hormones and their metabolites are potent inducers of δ-aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in the liver. In this study we examined the influences of a number of natural steroids on the induction of liver cytochrome P-450, δ-aminolevulinate synthase, and protoporphyrin in the chick embryo in ovo, and the effects of "priming" with a small dose of 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC), an inhibitor of ferrochelatase. There was a close relationship between the induction of cytochrome P-450 and δ-aminolevulinate synthase by steroids in experiments with, as well as in experiments without, DDC priming. In most instances, 5β steroids were more potent inducers than were the corresponding 5α epimers: 5β steroids more potently induced δ-aminolevulinate synthase and/or porphyrin accumulation for 11 of 15 steroid pairs tested and cytochrome P-450 for 10 of 14 pairs. With DDC priming, steroid induction of δ-aminolevulinate synthase and protoporphyrin was greatly accentuated, while the increase in cytochrome P-450 was partially prevented. This experimental model, is reminiscent of certain human porphyrias in which clinical expression is probably due in part to interactions of endogenous steroids with genetic deficiencies of heme pathway enzymes, and in which there is in the liver enhanced activity of δ-aminolevulinate synthase and accumulation of heme pathway intermediates, while hepatic cytochrome P-450 content is largely maintained. These features suggest that decreases in the regulatory "free" heme pool(s) in the liver can occur and produce pronounced δ-aminolevulinate synthase induction without the development of a marked deficiency of the major liver hemoprotein, cytochrome P-450.

AB - Certain steroid hormones and their metabolites are potent inducers of δ-aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in the liver. In this study we examined the influences of a number of natural steroids on the induction of liver cytochrome P-450, δ-aminolevulinate synthase, and protoporphyrin in the chick embryo in ovo, and the effects of "priming" with a small dose of 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC), an inhibitor of ferrochelatase. There was a close relationship between the induction of cytochrome P-450 and δ-aminolevulinate synthase by steroids in experiments with, as well as in experiments without, DDC priming. In most instances, 5β steroids were more potent inducers than were the corresponding 5α epimers: 5β steroids more potently induced δ-aminolevulinate synthase and/or porphyrin accumulation for 11 of 15 steroid pairs tested and cytochrome P-450 for 10 of 14 pairs. With DDC priming, steroid induction of δ-aminolevulinate synthase and protoporphyrin was greatly accentuated, while the increase in cytochrome P-450 was partially prevented. This experimental model, is reminiscent of certain human porphyrias in which clinical expression is probably due in part to interactions of endogenous steroids with genetic deficiencies of heme pathway enzymes, and in which there is in the liver enhanced activity of δ-aminolevulinate synthase and accumulation of heme pathway intermediates, while hepatic cytochrome P-450 content is largely maintained. These features suggest that decreases in the regulatory "free" heme pool(s) in the liver can occur and produce pronounced δ-aminolevulinate synthase induction without the development of a marked deficiency of the major liver hemoprotein, cytochrome P-450.

UR - http://www.scopus.com/inward/record.url?scp=0020456605&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0020456605&partnerID=8YFLogxK

U2 - 10.1016/0003-9861(82)90542-2

DO - 10.1016/0003-9861(82)90542-2

M3 - Article

VL - 217

SP - 597

EP - 608

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

IS - 2

ER -