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Tripeptide Aldehyde Protease Inhibitors May Depress in Vitro Prolactin and Growth Hormone Release^*

Heim Pál Pediatric Hospital Budapest, Hungary
Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
Chinoin Pharmaceutical Works Budapest, Hungary
The Institute for Drug Research Budapest, Hungary

Address all correspondence and requests for reprints to: Dr. Iván Nagy, Central Laboratory, Heim Pal Pediatric Hospital, H-1089 Budapest, Üllõi Street 86., Hungary.

Abstract

The effects of novel nontoxic tripeptide aldehyde inhibitors of proteolytic enzymes were examined in order to investigate the possibility that serine-thiol protease(s) may be involved in PRL and GH secretion. Rat anterior pituitary cells maintained in culture for 7–8 days or freshly taken pituitary quarters were treated with BOC-DPhe-Pro-Arg-H (BOCdPPA), DPhe-Pro-Arg-H (dPPA), BOC-DPhe-Leu-Lys-H (BOC-dPLL), or BOC-DPhe-Phe-Lys (BOC-dPPL). Newly synthetized [³H]PRL and [³H]GH as well as immunoreactive (i) hormones (iPRL, iGH) were measured in the incubation media and cell homogenates. Four hours of incubation in the presence of 0.1 mM dPPA resulted in a 30% decrease of [³H]PRL and iPRL release by cell cultures; the inhibition by BOC-dPPA was 60% and 48%, respectively. [³H]PRL biosynthesis was unchanged or slightly decreased. The effect of these tripeptide aldehydes on [³H]GH and iGH release was less pronounced but statistically significant. Pituitary quarters treated with 1.0 or 3.0 mM BOC-dPPA release 20% and 57% less [³H]PRL than the controls. In the same system BOC-dPPA in a 1.0 mM concentration did not effect GH secretion, and 3.0 mM BOC-dPPA inhibited [³H]GH output by 27%. Forty micromolars of BOCdPPL decreased by 47%, 0.2 mM by 79%, and 1.0 mM by 94% [³H]PRL release from pituitary quarters. GH secretion was not influenced. A similar selectivity was observed when BOC-dPLL was used. It is clear that by serine-thiol protease inhibitors whose effects are sequence and dose dependent, PRL and GH release are decreased. The relative inhibiting potency on PRL release was BOC-dPPL > BOC-dPLL > BOC-dPPA > dPPA. The biosynthesis of [³H]PRL was reduced only in the presence of the highest tripeptide aldehyde concentrations or long (8 h) exposure, and only 1.0 mM Boc-dPPL reduced [³H]GH biosynthesis by 30%. The data suggest that proteolysis may be involved in the process of PRL and GH release and the enzyme(s) in question may be serine-thiol protease(s). (Endocrinology 116: 1426–1432, 1985)

Footnotes

^* Part of this work was presented in preliminary form at the 4th International Congress on Prolactin, Charlottesville, VA, 1984 (Abstract 65).

Received July 18, 1984.