TY - JOUR
T1 - Selective induction of cytochrome P450 isozymes in rat liver by 4-n-alkyl-methylenedioxybenzenes
AU - Marcus, Craig B.
AU - Wilson, Neil M.
AU - Jefcoate, Colin R.
AU - Wilkinson, Christopher F.
AU - Omiecinski, Curtis J.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants GM-32281 and ES-04696 (to C.J.O.) and CA-16265 (to C.R.J.), and in part by American Cancer Society Institutional Grant IN-17 (to C.B.M.). N.M.W. was supported in part by National Institutes of Environmental Health Sciences Training Grant ES-07015 The authors thank Karen Rudd for her excellent technical assistance in portions of this work, and David Presser and Mattson Instruments for the FTIR analyses of synthetic methylenedioxybenzenes.
PY - 1990/2/15
Y1 - 1990/2/15
N2 - To examine the structural requirements of cytochrome P450 induction by 4-n-alkyl-substituted methylenedioxybenzenes (MDBs), rats were treated in vivo with a series of MDBs that differed in alkyl carbon sidechain length (0, 1, 2, 3, 4, 5, 6, or 8). Expression patterns of specific P450 isozymes were evaluated with Western and Northern blotting, enzymatic assays, and solution hybridization assays. As determined by carbon monoxide difference spectroscopy, maximal hepatic induction of total P450 content occurred when rats were treated with MDB derivatives with alkyl chain lengths of five or six carbons. However, maximum induction of the specific P450s-P450IA1, P450IIB1, and P450IIB2-occurred with n-hexyl-MDB. In contrast to effects observed with phenobarbital, treatment with MDBs resulted in higher levels of P450IIB2 than of P450IIB1 in rat hepatic microsomes. Western blot quantitation of MDB-induced hepatic P450IIB1 and P450IIB2 apoenzymes did not correlate to measured levels of the corresponding P450 mRNAs. In fact, P450IIB1 and P450IIB2 apoenzyme levels were consistently lower than expected based on Northern blot and solution hybridization measures of the respective mRNAs. These data suggest that the n-alkyl-MDBs effect increases in levels of hepatic P450 in a complex manner, producing accumulation of P450 mRNAs concomitant with alterations in processes regulating steady-state levels of P450 apoenzyme.
AB - To examine the structural requirements of cytochrome P450 induction by 4-n-alkyl-substituted methylenedioxybenzenes (MDBs), rats were treated in vivo with a series of MDBs that differed in alkyl carbon sidechain length (0, 1, 2, 3, 4, 5, 6, or 8). Expression patterns of specific P450 isozymes were evaluated with Western and Northern blotting, enzymatic assays, and solution hybridization assays. As determined by carbon monoxide difference spectroscopy, maximal hepatic induction of total P450 content occurred when rats were treated with MDB derivatives with alkyl chain lengths of five or six carbons. However, maximum induction of the specific P450s-P450IA1, P450IIB1, and P450IIB2-occurred with n-hexyl-MDB. In contrast to effects observed with phenobarbital, treatment with MDBs resulted in higher levels of P450IIB2 than of P450IIB1 in rat hepatic microsomes. Western blot quantitation of MDB-induced hepatic P450IIB1 and P450IIB2 apoenzymes did not correlate to measured levels of the corresponding P450 mRNAs. In fact, P450IIB1 and P450IIB2 apoenzyme levels were consistently lower than expected based on Northern blot and solution hybridization measures of the respective mRNAs. These data suggest that the n-alkyl-MDBs effect increases in levels of hepatic P450 in a complex manner, producing accumulation of P450 mRNAs concomitant with alterations in processes regulating steady-state levels of P450 apoenzyme.
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U2 - 10.1016/0003-9861(90)90543-8
DO - 10.1016/0003-9861(90)90543-8
M3 - Article
C2 - 2306127
AN - SCOPUS:0025156936
SN - 0003-9861
VL - 277
SP - 8
EP - 16
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 1
ER -