Cobalt-protoporphyrin, a synthetic heme analogue, feminizes hepatic androgen metabolism in the rat

A single injection of cobalt-protoporphyrin (50 mumol/kg) produced marked changes in the metabolism of 14C-labeled testosterone and 4-androstenedione by male rat liver microsomes and this effect was maintained for at least 3 weeks. The rate of 3 beta- and 5 alpha-reduction was increased to levels observed in untreated adult female animals and cobalt-protoporphyrin altered the metabolic profile of testosterone towards that observed after infusion of growth hormone whereas hypophysectomy produced a more general inhibition of androgen metabolism. The reduction of testosterone or 4-androstenedione by liver microsomes was also increased when cobalt-protoporphyrin (10-30 microM) was added in vitro but a higher concentration (100 microM) led to inhibition of androgen metabolism. The identity of the main androgen metabolites was established by TLC, HPLC and mass spectrometry and the role of 5 alpha-reductase was demonstrated using a specific inhibitor of this enzyme. The possible sites of action of cobalt-protoporphyrin are discussed in relation to its in vivo effects on serum testosterone and LH concentrations.