Metabolism of progesterone by the rabbit liver

The pathways of progesterone metabolism as well as the retention of specific unconjugated intermediates were determined in the liver of the 29-day-pregnant rabbit. At 40-45 min after iv administration of progesterone-4-¹⁴C, 4-6 % of the ¹⁴C dose was present in the liver. Of this approximately 1/6 was glucuronosides, 1/3 was sulfates and 1/2 was free steroids. Progesterone metabolites present in the free steroid pool of adult mammalian liver have not been previously identified; the pregnant rabbit retained 20α-hydroxypregn-4-en-3-one, 3α-hydroxy-5β- pregnan-20-one, 3β-hydroxy-5α-pregnan-20-one, 5α-pregnane-3β, 20α-diol, 5β-pregnane-3α, 20αdiol, 3α, 6ξ-dihydroxy-5α-pregnan-20-one and 5α pregnane- 3α, 6ξ, 20α:-triol. The last 2 compounds composed over 60 % of the labeled free steroids. The formation of metabolites of progesterone-4- ¹⁴C by surviving liver tissue slices was determined at several intervals in vitro. Progesterone metabolism was extremely rapid; only 15% of the substrate remained after 10 min. Generally, the type and concentration of metabolites in vivo could be predicted by their formation in vitro. The exception was 3β-hydroxy-5α-pregnan-20-one, which did not accumulate significantly at any time interval in vitro. Progesterone was metabolized in vitro almost exclusively via 3 pathways to 2 endproducts, 5/3-pregnane-3α, 20α-diol and 5α-pregnane- 3α, 6ξ, 20α-triol. The formation of 5/3-pregnane- 3α, 20α-diol can start either by Δ⁴-5β-reduction or by 20β-reduction. The A/B trans-pathway appears to be initiated by 6-hydroxylation of progesterone. Reductases capable of forming 3β- and 20β-hydroxy metabolites of progesterone were remarkably deficient in this tissue.