Multiple action of 2′-diethylaminoethyl 2,2-diphenylpentanoate HCl (SKF 525-A) on rat liver tryptophan pyrrolase in vivo

Abstract

SKF 525-A was observed to have an early stimulatory action in vivo on liver tryptophan pyrrolase activity in intact or adrenalectomized, but not hypophysectomized, male adult rats. The stimulatory effect was abolished by co-administration of actinomycin D, puromycin, or cycloheximide in intact animals, suggesting that SKF 525-A was inducing de novo formation of apo-tryptophan pyrrolase. Concurrent with stimulation of tryptophan pyrrolase in intact animals by SKF 525-A, there was a significant decrease in adrenal ascorbate. These effects of SKF 525-A on tryptophan pyrrolase or adrenal ascorbate were not seen in hypophysectomized rats. The stimulation of tryptophan pyrrolase activity by SKF 525-A would therefore seem to involve some form of pituitary activation. When SKF 525-A was co-administered with hydrocortisone, the stimulatory effects of the two agents were merely additive. However, administration of SKF 525-A to adrenalectomized rats receiving repeated injections of hydrocortisone markedly potentiated the inducing action of hydrocortisone. This enhancement of hydrocortisone induction occurred only if SKF 525-A was administered during the early tryptophan pyrrolase induction phase, i.e. prior to development of attenuation of hydrocortisone induction. Such an effect of SKF 525-A was not obtained in hypophysectomized rats undergoing similar treatments. SKF 525-A-like enhancement of hydrocortisone-induced tryptophan pyrrolase increases could also be produced by injection of saline homogenates of rat pituitary glands during the early tryptophan pyrrolase induction phase. Animals pretreated 12 hr before with SKF 525-A showed a reduced capacity to form new tryptophan pyrrolase after hydrocortisone administration. This late “anti-induc-tive” action of SKF 525-A was also seen for a second “stimulatory” dose of SKF 525-A but was not present for substrate stimulation of tryptophan pyrrolase (caused by injected tryptophan). These latter data indicate that SKF 525-A may reduce the ability of the liver to produce tryptophan pyrrolase from other than pre-existing mRNA template. It is concluded that SKF 525-A effects on hepatic tryptophan pyrrolase are multiple, ranging from hydrocortisone-like to actinomycin-like. No simple explanation for such diverse activities can be offered but this should serve as a caution to investigators who regard SKF 525-A as pharmacologically inert (Mannering, Ann. N.Y. Acad. Sci., 123, 108 (1965); Brodie et al., Science 148, 1547 (1965) or as a specific inhibitor of microsomal enzyme systems in liver.