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Complexation of cytochrome P-450 isozymes in hepatic microsomes from SKF 525-A-induced rats.
Arch Biochem Biophys. 1988 May 01; 262(2):381-8.AB

Abstract

Potassium ferricyanide-elicited reactivation of steroid hydroxylase activities, in hepatic microsomes from SKF 525-A-induced male rats, was used as an indicator of complex formation between individual cytochrome P-450 isozymes and the SKF 525-A metabolite. Induction of male rats with SKF 525-A (50 mg/kg for three days) led to apparent increases in androst-4-ene-3,17-dione 16 beta- and 6 beta-hydroxylation to 6.7- and 3-fold of control activities. Steroid 7 alpha-hydroxylase activity was decreased to 0.8-fold of control and 16 alpha-hydroxylation was unchanged. Ferricyanide-elicited dissociation of the SKF 525-A metabolite-P-450 complex revealed an even greater induction of 16 beta- and 6 beta-hydroxylase activities (to 1.8- and 1.6-fold of activities in the absence of ferricyanide). Androst-4-ene-3,17-dione 16 alpha-hydroxylase activity increased 2-fold after ferricyanide but 7 alpha-hydroxylase activity was unaltered. An antibody directed against the male-specific cytochrome P-450 UT-A decreased androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to 13% of control in hepatic microsomes from untreated rats. In contrast, 16 alpha-hydroxylase activity in microsomes from SKF 525-A-induced rats, before and after dissociation with ferricyanide, was reduced by anti UT-A IgG to 32 and 19% of the respective uninhibited controls. Considered together, these observations strongly suggest that the phenobarbital-inducible cytochrome P-450 isozymes PB-B and PCN-E are present in an inactive complexed state in microsomes from SKF 525-A-induced rat liver. Further, the increased susceptibility of androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to inhibition by an antibody to cytochrome P-450 UT-A, following ferricyanide treatment of microsomes, suggests that this male sexually differentiated enzyme is also complexed after in vivo SKF 525-A dosage. In contrast, the constitutive isozyme cytochrome P-450 UT-F, which is active in steroid 7 alpha-hydroxylation, does not appear to be complexed to any extent in microsomes from SKF 525-A-induced rats.

Authors+Show Affiliations

Murray M
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.

MeSH

AndrostenedioneAnimalsAryl Hydrocarbon HydroxylasesCytochrome P-450 Enzyme SystemCytochrome P450 Family 2Enzyme InductionFerricyanidesIsoenzymesMaleMicrosomes, LiverProadifenRatsRats, Inbred StrainsSteroid 16-alpha-HydroxylaseSteroid Hydroxylases

Pub Type(s)

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

Language

eng

PubMed ID

3364973

Citation

Murray, M. "Complexation of Cytochrome P-450 Isozymes in Hepatic Microsomes From SKF 525-A-induced Rats." Archives of Biochemistry and Biophysics, vol. 262, no. 2, 1988, pp. 381-8.
Murray M. Complexation of cytochrome P-450 isozymes in hepatic microsomes from SKF 525-A-induced rats. Arch Biochem Biophys. 1988;262(2):381-8.
Murray, M. (1988). Complexation of cytochrome P-450 isozymes in hepatic microsomes from SKF 525-A-induced rats. Archives of Biochemistry and Biophysics, 262(2), 381-8.
Murray M. Complexation of Cytochrome P-450 Isozymes in Hepatic Microsomes From SKF 525-A-induced Rats. Arch Biochem Biophys. 1988 May 1;262(2):381-8. PubMed PMID: 3364973.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Complexation of cytochrome P-450 isozymes in hepatic microsomes from SKF 525-A-induced rats. A1 - Murray,M, PY - 1988/5/1/pubmed PY - 1988/5/1/medline PY - 1988/5/1/entrez SP - 381 EP - 8 JF - Archives of biochemistry and biophysics JO - Arch Biochem Biophys VL - 262 IS - 2 N2 - Potassium ferricyanide-elicited reactivation of steroid hydroxylase activities, in hepatic microsomes from SKF 525-A-induced male rats, was used as an indicator of complex formation between individual cytochrome P-450 isozymes and the SKF 525-A metabolite. Induction of male rats with SKF 525-A (50 mg/kg for three days) led to apparent increases in androst-4-ene-3,17-dione 16 beta- and 6 beta-hydroxylation to 6.7- and 3-fold of control activities. Steroid 7 alpha-hydroxylase activity was decreased to 0.8-fold of control and 16 alpha-hydroxylation was unchanged. Ferricyanide-elicited dissociation of the SKF 525-A metabolite-P-450 complex revealed an even greater induction of 16 beta- and 6 beta-hydroxylase activities (to 1.8- and 1.6-fold of activities in the absence of ferricyanide). Androst-4-ene-3,17-dione 16 alpha-hydroxylase activity increased 2-fold after ferricyanide but 7 alpha-hydroxylase activity was unaltered. An antibody directed against the male-specific cytochrome P-450 UT-A decreased androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to 13% of control in hepatic microsomes from untreated rats. In contrast, 16 alpha-hydroxylase activity in microsomes from SKF 525-A-induced rats, before and after dissociation with ferricyanide, was reduced by anti UT-A IgG to 32 and 19% of the respective uninhibited controls. Considered together, these observations strongly suggest that the phenobarbital-inducible cytochrome P-450 isozymes PB-B and PCN-E are present in an inactive complexed state in microsomes from SKF 525-A-induced rat liver. Further, the increased susceptibility of androst-4-ene-3,17-dione 16 alpha-hydroxylase activity to inhibition by an antibody to cytochrome P-450 UT-A, following ferricyanide treatment of microsomes, suggests that this male sexually differentiated enzyme is also complexed after in vivo SKF 525-A dosage. In contrast, the constitutive isozyme cytochrome P-450 UT-F, which is active in steroid 7 alpha-hydroxylation, does not appear to be complexed to any extent in microsomes from SKF 525-A-induced rats. SN - 0003-9861 UR - https://www.unboundmedicine.com/medline/citation/3364973/Complexation_of_cytochrome_P_450_isozymes_in_hepatic_microsomes_from_SKF_525_A_induced_rats_ DB - PRIME DP - Unbound Medicine ER -