Induction of Cytochrome P - 450 by Nonclassical Receptor Mechanism 2009 9

In the companion report we used primary cultures of adult rat hepatocytes to demonstrate that glucocorticoids comprise a “classn of compounds that stimulate de novo synthesis of a form of cytochrome P-450 (P45opCN) indistinguishable from that induced by the nonhormonal steroid pregnenolone 16a-carbonitrile (PCN). Because induction of P45opCN is stereospecific for glucocorticoids and is dependent on the concentration of and the length of exposure to steroids it seemed possible that P45opCN represented another of the many genes whose expression is coordinately regulated by glucocorticoids bound to their specific cytoplasmic receptor and translocated into the nucleus. However, in cultured hepatocytes treated with glucocorticoids, synthesis of P45opCN failed to parallel synthesis of a typical glucocorticoid-responsive liver function, tyrosine aminotransferase, in the time course of induction, in the concentrations of glucocorticoids required for halfmaximal induction, and in the order of effective steroids ranked by potency. Indeed, two moderately potent inducers of P45OPcN either failed to induce tyrosine aminotransferase (spironolactone) or actually antagonized induction of tyrosine aminotransferase synthesis by glucocorticoids (PCN). Moreover, in the same cultures in which glucocorticoid induction of tyrosine aminotransferase was blocked by the presence of PCN or other previously identified antiglucocorticoids, synthesis of P45O&.CN was actually enhanced. We conclude that synthesis of P45opCN is a specific glucocorticoidresponsive liver function evoked by a novel mechanism readily distinguishable from the classic glucocorticoid receptor pathway.