Absorption and metabolism of topically applied testosterone in an organotypic skin culture.
The Living Skin Equivalent (LSE) is an organotypic coculture of human dermal fibroblasts in a collagen-containing matrix and a stratified epidermis composed of human epidermal keratinocytes. In order to establish the feasibility of using this in vitro system as a model for cutaneous biotransformation, the metabolic fate of topically applied testosterone (T) was monitored in the LSE. After a 24-hour exposure period (37 degrees C) to radiolabelled T, LSE extracts analyzed by high-performance thin-layer chromatography showed that approximately 50% of the applied T had been metabolized. Identified metabolites included bands which comigrated with polar metabolites and products of T 5 alpha-reductase. The general distribution of the observed metabolites was similar to that obtained using biopsied human skin. The rates of T penetration (32 degrees C) through the LSE were monitored after application of T in two vehicles (water and petrolatum) and yielded permeability constants (Kps) of 29 and 1.6 x 10(-3) cm/h, respectively. These Kp values were 4- to 6-fold higher than those reported for human abdominal skin, and reflect the vehicle-related shift in penetration seen in human skin. The Kp values for two additional steroids, estradiol and hydrocortisone, and for T were also determined at 22 degrees C and compared to published Kp values. These Kp values in the LSE were, respectively, 63-, 187- and 35-fold higher than those reported for human skin. The data suggest that compared to human skin the LSE has only a partial barrier function to the passage of test chemicals.(ABSTRACT TRUNCATED AT 250 WORDS)
Ernesti
A M
AM
Organogenesis Inc., Cambridge, Mass. 02142.
Swiderek
M
M
Gay
R
R
D000005:Abdomen; D000287:Administration, Topical; D000368:Aged; D000735:Androstenedione / Q000302:isolation & purification; D000738:Androsterone / Q000302:isolation & purification; D013196:Dihydrotestosterone / Q000302:isolation & purification / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007866:Leg; D008297:Male; D009924:Organ Culture Techniques; D012867:Skin / Q000033:anatomy & histology / Q000378:metabolism*; D012869:Skin Absorption; D013739:Testosterone / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D014020:Tissue Extracts / Q000737:chemistry
D014020:Tissue Extracts; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D000738:Androsterone