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Altered regulation of cytochrome P-450 enzymes in choline-deficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis.
Mol Pharmacol. 1987 Jan; 31(1):117-21.MP

Abstract

Total microsomal cytochrome P-450 levels were decreased, to about 50% of control, in liver of male rats made cirrhotic by the prolonged intake of a choline-deficient diet. We have suggested previously that this decrease in cytochrome P-450 levels is not a generalized one, but is selective for certain forms of the enzyme. In the present study, levels of six cytochrome P-450 forms including the sex-specific cytochrome P-450 forms, P-450UT-A, P-450PCN-E, and P-450UT-l, were quantitated immunochemically in hepatic microsomes prepared from control and cirrhotic male rats and were related to changes in the regioselectivity of cytochrome P-450-mediated androst-4-ene-3,17-dione hydroxylation in these fractions. The principal finding of this study was that the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase was decreased in cirrhotic microsomes to about 20% of control. The content of P-450UT-A decreased concurrently from about 0.40 to less than 0.01 nmol/mg of microsomal protein. Other pathways of androst-4-ene-3,17-dione hydroxylation were also affected, but to different extents than the 16 alpha-hydroxylase. 6 beta-Hydroxylation decreased in cirrhotic microsomes to about 45% of control, despite a marked decrease in P-450PCN-E from 0.27 to less than 0.002 nmol/mg of microsomal protein. The rate of androst-4-ene-3,17-dione 7 alpha-hydroxylation underwent a less pronounced reduction in cirrhosis to about two-thirds of control microsomal activity, and levels of the cytochrome P-450 associated with this activity, P-450UT-F, were decreased in proportion with the decrease in total microsomal cytochrome P-450. 16 beta-Hydroxylase activity was unaffected by the cirrhotogenic process. From spectral binding studies it was apparent that androst-4-ene-3,17-dione elicited a high affinity type I interaction in control microsomal fractions (Ks = 4.5 microM), whereas no interaction was apparent in cirrhotic liver microsomes. Levels of three other forms of cytochrome P-450--P-450PB-C (a constitutive form inducible by phenobarbital), P-450ISF-G (a major isosafrole-inducible form), and P-450UT-I (the major female sexually-differentiated isozyme)--were apparently unaltered in cirrhosis. These findings are consistent with the assertion that specific forms of cytochrome P-450 are subject to altered regulation in hepatic cirrhosis.

Authors

Murray M
No affiliation info available
Zaluzny L
No affiliation info available
Dannan GA
No affiliation info available
Guengerich FP
No affiliation info available
Farrell GC
No affiliation info available

MeSH

AndrostenedioneAnimalsCholine DeficiencyCytochrome P-450 Enzyme SystemImmunosorbent TechniquesLiver Cirrhosis, ExperimentalMaleMicrosomes, LiverRatsSpectrum AnalysisSteroid Hydroxylases

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

3543647

Citation

Murray, M, et al. "Altered Regulation of Cytochrome P-450 Enzymes in Choline-deficient Cirrhotic Male Rat Liver: Impaired Regulation and Activity of the Male-specific Androst-4-ene-3,17-dione 16 Alpha-hydroxylase, Cytochrome P-450UT-A, in Hepatic Cirrhosis." Molecular Pharmacology, vol. 31, no. 1, 1987, pp. 117-21.
Murray M, Zaluzny L, Dannan GA, et al. Altered regulation of cytochrome P-450 enzymes in choline-deficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis. Mol Pharmacol. 1987;31(1):117-21.
Murray, M., Zaluzny, L., Dannan, G. A., Guengerich, F. P., & Farrell, G. C. (1987). Altered regulation of cytochrome P-450 enzymes in choline-deficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis. Molecular Pharmacology, 31(1), 117-21.
Murray M, et al. Altered Regulation of Cytochrome P-450 Enzymes in Choline-deficient Cirrhotic Male Rat Liver: Impaired Regulation and Activity of the Male-specific Androst-4-ene-3,17-dione 16 Alpha-hydroxylase, Cytochrome P-450UT-A, in Hepatic Cirrhosis. Mol Pharmacol. 1987;31(1):117-21. PubMed PMID: 3543647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altered regulation of cytochrome P-450 enzymes in choline-deficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis. AU - Murray,M, AU - Zaluzny,L, AU - Dannan,G A, AU - Guengerich,F P, AU - Farrell,G C, PY - 1987/1/1/pubmed PY - 1987/1/1/medline PY - 1987/1/1/entrez SP - 117 EP - 21 JF - Molecular pharmacology JO - Mol Pharmacol VL - 31 IS - 1 N2 - Total microsomal cytochrome P-450 levels were decreased, to about 50% of control, in liver of male rats made cirrhotic by the prolonged intake of a choline-deficient diet. We have suggested previously that this decrease in cytochrome P-450 levels is not a generalized one, but is selective for certain forms of the enzyme. In the present study, levels of six cytochrome P-450 forms including the sex-specific cytochrome P-450 forms, P-450UT-A, P-450PCN-E, and P-450UT-l, were quantitated immunochemically in hepatic microsomes prepared from control and cirrhotic male rats and were related to changes in the regioselectivity of cytochrome P-450-mediated androst-4-ene-3,17-dione hydroxylation in these fractions. The principal finding of this study was that the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase was decreased in cirrhotic microsomes to about 20% of control. The content of P-450UT-A decreased concurrently from about 0.40 to less than 0.01 nmol/mg of microsomal protein. Other pathways of androst-4-ene-3,17-dione hydroxylation were also affected, but to different extents than the 16 alpha-hydroxylase. 6 beta-Hydroxylation decreased in cirrhotic microsomes to about 45% of control, despite a marked decrease in P-450PCN-E from 0.27 to less than 0.002 nmol/mg of microsomal protein. The rate of androst-4-ene-3,17-dione 7 alpha-hydroxylation underwent a less pronounced reduction in cirrhosis to about two-thirds of control microsomal activity, and levels of the cytochrome P-450 associated with this activity, P-450UT-F, were decreased in proportion with the decrease in total microsomal cytochrome P-450. 16 beta-Hydroxylase activity was unaffected by the cirrhotogenic process. From spectral binding studies it was apparent that androst-4-ene-3,17-dione elicited a high affinity type I interaction in control microsomal fractions (Ks = 4.5 microM), whereas no interaction was apparent in cirrhotic liver microsomes. Levels of three other forms of cytochrome P-450--P-450PB-C (a constitutive form inducible by phenobarbital), P-450ISF-G (a major isosafrole-inducible form), and P-450UT-I (the major female sexually-differentiated isozyme)--were apparently unaltered in cirrhosis. These findings are consistent with the assertion that specific forms of cytochrome P-450 are subject to altered regulation in hepatic cirrhosis. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/3543647/Altered_regulation_of_cytochrome_P_450_enzymes_in_choline_deficient_cirrhotic_male_rat_liver:_impaired_regulation_and_activity_of_the_male_specific_androst_4_ene_317_dione_16_alpha_hydroxylase_cytochrome_P_450UT_A_in_hepatic_cirrhosis_ DB - PRIME DP - Unbound Medicine ER -