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MOLECULAR ACTIONS OF GIBBERELLIC ACID AND DELTA-1-TETRAHYDROCANNABINOL IN THE IMMATURE RAT UTERUS
Two endogenous plant compounds, (DELTA)-1-tetrahydrocannabinol (THC) and gibberellic acid (GA), have been reported to have endocrine effects in mammals. THC, the psychotomimetic constituent of marijuana, has been reported to influence the male reproductive system in several animal species. Its effects were manifested in a loss of testosterone biosynthesis in Leydig cells and in a decrease in pituitary output of luteinizing hormone and follicle stimulating hormone. Similar studies in the female have not shown a consistent pattern, especially the current controversy of estrogen-like activity of THC upon the reproductive tract and accessory sex organs. THC has been reported to have estrogenic activity in the female rat by several investigators. Several other groups have reported no such activity in the rat uterus, mouse mammary tissue, and uterine tissue from the rhesus monkey. To date, no definitive study has been undertaken in one animal species, monitoring several endpoints of estrogen activity, to resolve this conflict. GA has also been implicated in possessing hormonal activity, namely, glucocorticoid-like activity under conditions of stress, restoration of the reproductive tract histology in ovariectomized rats, and weak estrogenic activity and estrogen synergism in mice. There have been no reports of the biochemical mechanism of GA action. In order to ascertain if either of these compounds had estrogenic or antiestrogenic activity and if so, the molecular mechanism of action, three indicators of estrogenic activity were investigated in the immature female rat. Temporally, these indicators were the competition for the cytosolic estrogen receptor protein, the in vitro synthesis of an estrogen-enhanced protein (IP) and the in vivo uterine wet and dry weight gain. These indicators encompassed estrogenic responses from the initial physicochemical event to the ultimate expression of uterine mitotic activity. In the immature rat system, the cytosolic estrogen receptor showed saturation kinetics with a K(,d) of 3 x 10('-10)M and a maximal number of binding sites of 35 pmol/g uterine tissue. This binding was competitive with unlabeled estradiol. The estrogen-enhanced IP synthesis was monitored by polyacrylamide gel electrophoresis. Maximal induction appeared as an increase in the protein ('3)H/('14)C leucine-incorporation ratio with a relative mobility (R(,m)) of 0.65. Subcutaneous administration of estradiol resulted in a significant increase in both wet and dry uterine weight following a three-day dosage regimen. Competition for the cytosolic estrogen receptor was not observed with either THC or GA over a concentration range of 10('-10) to 10('-6)M. Neither compound was able to elicit IP synthesis at a concentration of 10('-5)M as reflected in a ('3)H/('14)C baseline curve at R(,m) 0.65. Neither compound was able to elicit any significant increase in uterine wet and dry weight when administered at 2 and 10mg/kg body weight. When co-administered with estradiol, no antagonism was seen. There did appear to be a slight synergism with estradiol but further investigation showed this to be insignificant. Neither THC nor GA appeared estrogenic in tests for estrogen responsiveness in rat uterine tissue under the experimental conditions imposed. Since the animal population investigated was immature, it is possible that these compounds may express estrogen-like activity at later stages of development. Perhaps the appearance of a mature drug metabolizing system with consequent biotransformation could explain some of the conflicts reported in the literature.
NAGLE, JOHN DAVID, "MOLECULAR ACTIONS OF GIBBERELLIC ACID AND DELTA-1-TETRAHYDROCANNABINOL IN THE IMMATURE RAT UTERUS" (1981). Doctoral Dissertations Available from Proquest. AAI8118030.