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Influence of indole carbinols and growth hormone on the metabolism of 4-androstenedione by rat liver microsomes.
J Steroid Biochem Mol Biol. 1993 Dec; 46(6):791-8.JS

Abstract

The effect of indole-3-carbinol (IC), an anticarcinogen present in cruciferous vegetables, to alter the metabolism of 4-androstenedione (AD) by female rat liver microsomes was investigated and compared to that of its main gastric conversion product, diindolylmethane (DIM) as well as other specific cytochrome P450 inducers. DIM was a more potent inducer of the hydroxylase which converts androsterone to its 6 beta-hydroxylated derivative 3 alpha, 6 beta-dihydroxy-5 alpha-androstan-17-one (A) than IC after either oral or intraperitoneal administration and was also a better in vitro inhibitor. Isosafrole (ISF), which like IC and DIM, induces CYP1A2 as well as gestodene, were powerful inhibitors of the in vitro reaction. Naringenin produced only a weak inhibitory effect while 3-methylcholanthrene was inactive. SKF-525A, a prototypic hydroxylase inhibitor, or 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androst-1-ene-3-one which inhibits steroid 5 alpha-reductase, also decreased the formation of A from AD by liver microsomes. The infusion of human growth hormone by osmotic minipump, which feminizes hepatic steroid metabolism, increased the ability of male rat liver microsomes to convert AD to A and to respond to induction by IC. The identity of A, the main polar derivative of AD, induced by IC, DIM and ISF, was tentatively assigned by a combination of GC-MS and results from metabolic studies with intermediates in the pathway leading to its formation. It is proposed that the protective role of indole carbinols against mammary carcinoma due to decreased formation of 16 alpha-hydroxyestrone from estrone may be further enhanced by the diminished availability of AD for aromatization to estrone.

Authors+Show Affiliations

Jellinck PH
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Makin HL
No affiliation info available
Sepkovic DW
No affiliation info available
Bradlow HL
No affiliation info available

MeSH

Administration, OralAndrostenedioneAnimalsAnticarcinogenic AgentsBenzoflavonesBiotransformationCytochrome P-450 Enzyme SystemEnzyme InductionFemaleGrowth HormoneIndolesInjections, IntraperitonealKineticsMaleMicrosomes, LiverRatsRats, Sprague-DawleySafroleSex FactorsStructure-Activity Relationshipbeta-Naphthoflavone

Pub Type(s)

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

Language

eng

PubMed ID

8274413

Citation

Jellinck, P H., et al. "Influence of Indole Carbinols and Growth Hormone On the Metabolism of 4-androstenedione By Rat Liver Microsomes." The Journal of Steroid Biochemistry and Molecular Biology, vol. 46, no. 6, 1993, pp. 791-8.
Jellinck PH, Makin HL, Sepkovic DW, et al. Influence of indole carbinols and growth hormone on the metabolism of 4-androstenedione by rat liver microsomes. J Steroid Biochem Mol Biol. 1993;46(6):791-8.
Jellinck, P. H., Makin, H. L., Sepkovic, D. W., & Bradlow, H. L. (1993). Influence of indole carbinols and growth hormone on the metabolism of 4-androstenedione by rat liver microsomes. The Journal of Steroid Biochemistry and Molecular Biology, 46(6), 791-8.
Jellinck PH, et al. Influence of Indole Carbinols and Growth Hormone On the Metabolism of 4-androstenedione By Rat Liver Microsomes. J Steroid Biochem Mol Biol. 1993;46(6):791-8. PubMed PMID: 8274413.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influence of indole carbinols and growth hormone on the metabolism of 4-androstenedione by rat liver microsomes. AU - Jellinck,P H, AU - Makin,H L, AU - Sepkovic,D W, AU - Bradlow,H L, PY - 1993/12/1/pubmed PY - 1993/12/1/medline PY - 1993/12/1/entrez SP - 791 EP - 8 JF - The Journal of steroid biochemistry and molecular biology JO - J Steroid Biochem Mol Biol VL - 46 IS - 6 N2 - The effect of indole-3-carbinol (IC), an anticarcinogen present in cruciferous vegetables, to alter the metabolism of 4-androstenedione (AD) by female rat liver microsomes was investigated and compared to that of its main gastric conversion product, diindolylmethane (DIM) as well as other specific cytochrome P450 inducers. DIM was a more potent inducer of the hydroxylase which converts androsterone to its 6 beta-hydroxylated derivative 3 alpha, 6 beta-dihydroxy-5 alpha-androstan-17-one (A) than IC after either oral or intraperitoneal administration and was also a better in vitro inhibitor. Isosafrole (ISF), which like IC and DIM, induces CYP1A2 as well as gestodene, were powerful inhibitors of the in vitro reaction. Naringenin produced only a weak inhibitory effect while 3-methylcholanthrene was inactive. SKF-525A, a prototypic hydroxylase inhibitor, or 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androst-1-ene-3-one which inhibits steroid 5 alpha-reductase, also decreased the formation of A from AD by liver microsomes. The infusion of human growth hormone by osmotic minipump, which feminizes hepatic steroid metabolism, increased the ability of male rat liver microsomes to convert AD to A and to respond to induction by IC. The identity of A, the main polar derivative of AD, induced by IC, DIM and ISF, was tentatively assigned by a combination of GC-MS and results from metabolic studies with intermediates in the pathway leading to its formation. It is proposed that the protective role of indole carbinols against mammary carcinoma due to decreased formation of 16 alpha-hydroxyestrone from estrone may be further enhanced by the diminished availability of AD for aromatization to estrone. SN - 0960-0760 UR - https://www.unboundmedicine.com/medline/citation/8274413/Influence_of_indole_carbinols_and_growth_hormone_on_the_metabolism_of_4_androstenedione_by_rat_liver_microsomes_ L2 - https://www.lens.org/lens/search/patent/list?q=citation_id:8274413 DB - PRIME DP - Unbound Medicine ER -