Sebum-suppressing activity of the nonpolar arotinoid Ro 15-0778 in rodents

Summary

Retinoids are known to modulate sebaceous gland activity in humans and animals. The nonpolar arotinoid Ro 15-0778 [(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methyl-2-phenylethenyl) naphthalene] does not contain a polar end group and is devoid of the classical retinoid side effects of hypervitaminosis A. The favorable toxicological profile stimulated the evaluation of this arotinoid in animal models of sebum production. In castrated, testosterone-stimulated male rats, Ro 15-0778 is 50 times more potent than 13-cis-retinoic acid in inhibiting the production and subsequent secretion of sebum. The oral ED₅₀ value of Ro 15-0778 is 30μg/kg, while an oral dose of 0.5 mg/kg inhibited sebum secretion nearly 1005. In testosterone-stimulated female rats, Ro 15-0778 inhibits sebum secretion significantly with an oral ED₅₀ of 140 μg/kg and an s.c. ED₅₀ of 75μg/kg. Ro 15-0778 was also evaluated for its ability to prevent testosterone induction of the immature hamster flank organ. The topical ED₅₀ is 0.53 mg/kg and the oral ED₅₀ is 38 mg/kg. This arotinoid is similarly active in mature male hamsters without testosterone treatment. In addition, the retinoid is active topically and orally in reducing the size of the gerbil abdominal sebaceous gland. The compound exhibits no antiandrogenic activity when tested in ventral prostrate and seminal vesicle assays in rats. Additionally, the compound does not have estrogenic activity when tested in the rat uterine weight assay. High doses of Ro 15-0778 in humans did not demonstrate significant sebumsuppressing activity. This study indicates that extra-polation of retinoid data from rodent animal models to activity in human sebaceous glands can not be made with a high degree of certainty. There is a need to develop new, more predictive models for retinoid activity.