Induction and repression of microsomal drug-metabolizing enzymes by polycyclic hydrocarbons and phenobarbital: Theoretical models

Abstract

Administration to animals of polycyclic hydrocarbons (e.g. 3-methylcholanthrene) and drugs (e.g. phenobarbital) stimulates many hepatic microsomal mixed-function oxidases and inhibits a few others. Evidence indicating the “induction” of aminoazo dye N-demethylase and other mixed-function oxidases, and “repression” of the dimethylnitrosamine-demethylase by 3-methylcholanthrene (and other polynuclear hydrocarbons) is discussed. The well-known stimulatory effects of 3-methylcholanthrene on several events, both nuclear and cytoplasmic, in protein synthesis, indicate a highly specific and selective role in the differential effects of this hydrocarbon on the synthesis of mixed-function oxidases. Such selectivity could bring about differences in the output of messenger RNA molecules serving as templates for “inducible” and “repressible” enzymes. Alternative theoretical models are proposed to account for the differential effect of “inducers” in enhancing the synthesis of many and repressing the synthesis of some microsomal mixed-function oxidases. The following models are based on transcriptional control: (i) 3-methylcholanthrene is an “inducer” which allosterically combines with and inactivates the “active repressor”, thereby leading to “derepression” in the case of “inducible” enzymes; it acts as “corepressor” and activates the otherwise “inactive repressor” in the case of “repressible” enzymes; (ii) the above model may be extended to “cascade control”: the hydrocarbon inactivates the “active repressor” and, thereby, turns “on” one or more operon(s) which carry the structural genes coding for “inducible” enzymes and also a regulator gene which synthesizes a repressor turning “off” a second group of operon(s) carrying the structural genes coding for “repressible” enzymes; (iii) there is little evidence-if any-at present that hydrocarbons might modulate the regulatory role of histones (by modifying, e.g., acetylation) and thus switch “on” or “off” sets of genes. As an alternative, translational mode of control needs to be considered. 3-Methylcholanthrene may direct, in the case of inducible enzymes, the “right” folding-up of the nascent polypeptide chain and facilitate protein synthesis on the ribosomes. At the template of “repressible” enzymes, the hydrocarbon promotes the “wrong” conformation and, hence, synthesis of enzyme protein on the ribosomes is hindered.