FAILURE OF CANNABINOID COMPOUNDS TO STIMULATE ESTROGEN-RECEPTORS

Delta(9)-Tetrahydrocannabinol (THC), the primary active compound in Ca nnabis sativa (marihuana), and other cannabinoid receptor agonists exe rt potent effects on luteinizing hormone and prolactin release in anim al models and humans. Compounds possessing the tricyclic cannabinoid s tructure, including Delta(9)-THC and cannabidiol, have been reported t o interact with rodent uterine estrogen receptors in ligand binding as says. The present study tested the hypothesis that cannabinoid compoun ds produce a direct activation of estrogen receptors. We investigated whether cannabinoid compounds exhibit estrogen-induced mitogenesis in MCF-7 breast cancer cells. Under conditions in which 10 pM estradiol p romoted MCF-7 cell proliferation, no response was observed with biolog ically relevant concentrations (less than or equal to 10 mu M) of Delt a(9)-THC or its tricyclic analog desacetyllevonantradol. No response w as observed with cannabidiol, a bicyclic cannabinoid compound that exh ibits no cannabimimetic behavioral effects but has been reported to bi nd to the estrogen receptor in vitro. Delta(9)-THC also failed to anta gonize the response to estradiol under conditions in which the antiest rogen LY156758 (keoxifene; raloxifene) was effective. The phytoestroge n formononetin behaved as an estrogen at high concentrations, and this response was antagonized by LY156758. We also investigated the abilit y of cannabinoid compounds to stimulate transcription of an EREtkCAT r eporter gene transiently transfected into MCF-7 cells. Neither Delta(9 )-THC, desacetyllevonantradol, nor cannabidiol stimulated transcriptio nal activity. We conclude that psychoactive or inactive compounds of t he cannabinoid structural class fail to behave as agonists in appropri ate assays of estrogen receptor responses in vitro. Copyright (C) 1996 Elsevier Science Inc.