title: Caffeine, theophylline, theobromine, and developmental growth of the mouse mammary gland.
abstract: The purpose of this study was to determine the comparative activities of three methylxanthines, i.e., 1,3,7-trimethylxanthine (caffeine), 1,3-dimethylxanthine (theophylline), and 3,7-dimethylxanthine (theobromine) on developmental growth of the mammary gland in ovarian-hormone treated, mature nulliparous female Balb/c mice. When caffeine or theophylline was administered daily (via drinking water, 500 mg/L) for 30 days to 17 beta-estradiol/progesterone-treated intact or ovariectomized mice, a significant (p less than 0.05) enhancement of hormone-induced mammary gland lobulo-alveolar differentiation was observed. Caffeine or theophylline thus accelerated and/or intensified mammae lobulo-alveolar differentiation induced by the ovarian steroids. In contrast, theobromine (500 mg/L drinking water) did not significantly modify this developmental process. The stimulatory effect of caffeine and theophylline on mammae development was comparable quantitatively. In an effort to determine whether or not the stimulatory effect of caffeine or theophylline was directly on the mammary gland, small slow-release Elvax-40P pellets containing these methylxanthines were implanted directly into the mammary gland of mice concurrently treated with estrogen and progesterone. No significant stimulatory effect of caffeine or theophylline (or theobromine) was observed. Furthermore, the addition of methylxanthines (caffeine, 100 microM) to the culture media of whole mouse mammary glands (organ cultures) did not enhance lobulo-alveolar differentiation induced by mammotrophic hormones. Thus, while a consistent significant stimulatory effect of caffeine and theophylline on mammary lobulo/alveolar differentiation was observed when the methylxanthines were consumed orally (drinking water), no direct effect of these methylxanthines, when placed directly into the mammary gland or in culture media, on mammae development was observed. These data demonstrate that certain methylxanthines (e.g., caffeine and theophylline) but not others (e.g., theobromine) can significantly enhance mammotrophic hormone-induced mammary lobulo-alveolar differentiation in female Balb/c mice, an effect that appears not to be manifested via a direct action of the methylxanthines on the mammary gland.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
authors.forename: L C
authors.initials: LC
authors.lastname: VanderPloeg
authors.forename: D M
authors.initials: DM
authors.lastname: Wolfrom
authors.forename: A R
authors.initials: AR
authors.lastname: Rao
authors.forename: W E
authors.initials: WE
authors.lastname: Braselton
authors.forename: C W
authors.initials: CW
authors.lastname: Welsch
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D002110:Caffeine / Q000097:blood / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004343:Drug Implants; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D007091:Image Processing, Computer-Assisted; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology; D013805:Theobromine / Q000097:blood / Q000494:pharmacology*; D013806:Theophylline / Q000097:blood / Q000494:pharmacology*
chemical_list: D004343:Drug Implants; D004967:Estrogens; D002110:Caffeine; D011374:Progesterone; D013806:Theophylline; D013805:Theobromine