Androgen Inactivation in Human Lung Fibroblasts: Variations in Levels of 17-Hydroxysteroid Dehydrogenase Type 2 and 5-Reductase Activity Compatible with Androgen Inactivation

Androgens delay lung maturation through their action on lung fibroblasts. Knowing that testosterone is secreted by the lung epithelial-like cell line A-549, we have studied the metabolism of androgens by several human lung diploid fibroblasts cell lines. No 17-ketosteroid reductase activity was detected. In contrast, testosterone was transformed mainly into androstenedione and androstanedione with no 5alpha-dihydrotestosterone formed, indicating the presence of 17beta-hydroxysteroid. dehydrogenase (HSD) type 2 and 5alpha-reductase activities. The eight cell lines analyzed had either a low or high 17beta-HSD type 2 activity level. No correlation between these levels and the sex or age stage of cells was established, but Northern blot analysis of human lung RNA samples of five adult subjects revealed very similar variations between subjects in the level of 17beta-HSD type 2 mRNA. The 5alpha-reductase activity had a marked substrate preference for androstenedione, the product of 17beta-HSD type 2. When, tritiated testosterone was used as substrate, only barely detectable levels of 5alpha-dihydrotestosterone were observed by HPLC in the presence of the 17beta-HSD type 2 inhibitor EM-919. The use of unlabeled testosterone or of the antiandrogen hydroxyflutainide demonstrated that the tritiated testosterone substrate itself had no effect on levels of 5alpha-reduction. In fact, in these cells, 5alpha-reductase has no significant activity on testosterone, but it further converts the product of 17beta-HSD type 2, thus playing a role with 17beta-HSD type 2 in androgen inactivation. Because androgens delay lung maturation and surfactant synthesis by their action on lung fibroblasts, it is of particular interest to find that the steroid metabolism of these lung fibroblast cells is oriented toward androgen inactivation. Because lung fibroblasts of subjects with low 17beta-HSD type 2 expression levels are likely to be exposed to higher levels of androgens, an allelic variation of the 17beta-HSD-2 gene is suspected, which would result in familial incidence of respiratory distress. This is in line with reported cases of familial incidence of respirafory distress.