SPECIFIC BINDING, STIMULATION OF RODENT URINARY-BLADDER EPITHELIAL ORNITHINE DECARBOXYLASE, AND INDUCTION OF TRANSITIONAL CELL HYPERPLASIA BY THE SKIN TUMOR PROMOTER 12-O-TETRADECANOYLPHORBOL-13-ACETATE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (12) , 5964-5971
Abstract
The effects of intraurethral or i.p. administration of a mouse skin tumor promoter phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), on rodent urinary bladder transitional epithelium were studied. TPA, when instilled into the urinary bladder of inbred rats (female Fischer, F344) or mice (C3H, ICR, C57BL .times. DBA/2 F1) at a dose as low as 0.16 nmol, led to a significant (.apprx. 10-fold) increase in bladder ornithine decarboxylase (EC 4.1.1.17) (ODC) activity. Peak ODC activity was observed at .apprx. 6 h, and enzyme activity returned to base levels .apprx. 14 h after intravesical TPA. Administration of TPA i.p. in dimethyl sulfoxide also induced vesical ODC at 4 h after treatment. The magnitude of vesical ODC induction correlated well with the ability of a series of phorbol esters to promote mouse skin tumor formation (TPA > phorbol didecanoate > phorbol dibenzoate, and phorbol diacetate or phorbol did not induce bladder ODC activity). Mezerein, a 2nd stage mouse skin tumor promoter, induced urinary bladder ODC as much as TPA did. Increased ODC activity by TPA was the result of an increased amount of ODC protein localized mostly (> 60%) in urinary bladder mucosa. Intraurethrally administered TPA induced transitional cell hyperplasia starting at Day 2, and it persisted for about 7 days. The urothelium regained normal histology 13 days after TPA treatment. TPA bound specifically and with high affinity to murine bladder mucosa and muscularis particulate preparations. Scatchard analysis of mucosal binding revealed a Kd of 0.82 nM; at saturation, 2.43 pmol were bound per mg protein. Since TPA binds specifically to urinary bladder epithelium, and the induction of ODC activity is one of the properties of tumor promoters, one may conclude that TPA may promote urinary bladder carcinogenesis. Intravesical saccharin also induced urinary bladder ODC activity, but TPA at equimolar quantity was far more potent than saccharin. Thus, TPA, being a structurally well-defined molecule, may be a useful compound to study the phenomenon of the tumor promotion stage in urinary bladder carcinogenesis.