Oxidoreductive and hydroxylating metabolism of progesterone in rat liver epithelial cell lines

Abstract

Mechanisms and sequences of reduction and hydroxylation of progesterone into 6-hydroxypregnanolones were studied in proliferating rat liver epithelial cell cultures. These cell lines had an intense metabolic activity and all the metabolites were unconjugated. The formation of 3α,6α- and 3β,6α-dihydroxy-5α-pregnan-20-one was observed when the cells were incubated with progesterone, 5α-pregnane-3,20-dione, 3α- or 3β-hydroxy-5α-pregnan-20-one and 6α-hydroxy-5α-pregnane-3,20-dione but not with 6α- or 6β-hydroxyprogesterone, 5β-pregnane-3,20-dione, 3α- or 3β-hydroxy-5β-pregnan-20-one. These findings indicate that the potential precursors of the 6α-hydroxypregnanolones have a 5α-configuration. The reduction of 5α-pregnane-3,20-dione at C-3 followed by a 6α-hydroxylation can be postulated as the major, if not the only, metabolic pathway. However, the possibility that 6α-hydroxylation may occur prior to reduction of the C-3 oxo group cannot be entirely ruled out. The stereospecificity of reduction at C-5 and hydroxylation at C-6 are discussed and compared with 6-hydroxylated progesterone metabolites found in man and some other mammals during pregnancy and the neonatal period.