Methoxyresorufin: an inappropriate substrate for cyp1a2 in the mouse

Hepatic microsomes derived from Cyp1 a2(−/−) knockout (KO) and parental strains of mice, C57BL/6N and 129Sv, were used to examine the specificity of methoxyresorufin and acetanilide as substrates for CYP1A2 activity. In addition, animals from each group were exposed to CYP1-inducing compounds. As ex...

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Bibliographic Details
Published in:Biochemical pharmacology 1998-12, Vol.56 (12), p.1657-1660
Main Authors: Hamm, Jonathan T, Ross, David G, Richardson, Vicki M, Diliberto, Janet J, Birnbaum, Linda S
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Aryl Hydrocarbon Hydroxylases - biosynthesis
Aryl Hydrocarbon Hydroxylases - metabolism
Benzofurans
Biological and medical sciences
CYP1A2
Cytochrome P-450 CYP1A1 - biosynthesis
Cytochrome P-450 CYP1A1 - metabolism
Cytochrome P-450 CYP1A2 - biosynthesis
Cytochrome P-450 CYP1A2 - metabolism
Cytochrome P-450 Enzyme System - biosynthesis
Cytochrome P-450 Enzyme System - metabolism
Enzyme Induction
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Male
methoxyresorufin
Mice
Mice, Inbred Strains
Mice, Knockout
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
mouse
Oxazines - metabolism
Oxidoreductases
Oxidoreductases - biosynthesis
Oxidoreductases - metabolism
Polychlorinated Biphenyls
Polychlorinated Dibenzodioxins
Substrate Specificity
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Summary:Hepatic microsomes derived from Cyp1 a2(−/−) knockout (KO) and parental strains of mice, C57BL/6N and 129Sv, were used to examine the specificity of methoxyresorufin and acetanilide as substrates for CYP1A2 activity. In addition, animals from each group were exposed to CYP1-inducing compounds. As expected, microsomes from untreated 1 a2 KO mice did not have immunodetectable CYP1A2 protein; however, methoxyresorufin- O-demethylase (MROD, 25.5 ± 6.1 pmol/min/mg protein) and acetanilide-4-hydroxylation (ACOH, 0.64 ± 0.04 nmol/min/mg protein) activities were still present. Furthermore, induction of ethoxyresorufin- O-deethylase (EROD) by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in 1 a2 KO mice was accompanied by a greater than 70-fold increase in MROD activity. In contrast, ACOH was only induced 2-fold by TCDD. As with 1 a2 KO mice, the parental strains exposed to TCDD or 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) showed substantial EROD and MROD induction, whereas ACOH activity was induced to a lesser degree. PCB153 (2,2′,4,4′,5,5′-hexachlorobiphenyl) resulted in low levels of both EROD and MROD induction. Results indicate that both substrates are subject to metabolism by non-CYP1A2 sources, and the apparent contribution of CYP1A1 activity to methoxyresorufin metabolism makes MROD unsuitable for differentiating CYP1A1 and CYP1A2 activities in the mouse.
ISSN:0006-2952
1873-2968
DOI:10.1016/S0006-2952(98)00241-X