The metabolism of 6,7-3H-tabelled 3-propyl ether estradiol (PE2) and of [6,7-3H]estradiol was studied by rat liver perfusion under different experimental conditions. In all cases, 90% of the radioactivity was retained in the liver, indicating an active uptake by the liver. The hepatic radioactivity was slowly released at a constant rate in the efferent perfusate. The proportion of radioactive metabolites in the perfusate was approximately the same as in the liver.3-Propyl ether estrone (PE1), a dehydrogenation product of PE2, and 3-propyl ether estriol (PE3), a 16α-hydroxylated derivative of PE2, were identified. Propylated metabolites more polar than PE2 were found. A low amount of propylated metabolites was conjugated with the exception of PE1. From the appearance of phenolic steroids including estrone, estradiol, and estriol, it was concluded that cleavage of the 3-propyl ether group had occurred.Compared with perfusion under oxygen, the overall metabolism was significantly reduced when the perfusion was carried out under nitrogen which demonstrates that oxygen plays a part in all the enzymatic systems involved. When animals were stimulated by phenobarbital, their entire metabolism was activated. These results suggest a metabolism mainly located in the hepatic microsomes.Our results show that the propylated hormone is metabolized like the free hormone. However, the transformations of PE2 are slower when compared with estradiol: thus, the 3-propyl ether group provided some hormone protection against hepatic degradation.
The transcutaneous penetration of 3-propyl ether, 17-methyl ether oestradiol (POM) occurs by a diffusion phenomenon and does not seem to be modulated by a cutaneous receptor as it is the case for oestradiol. After transcutaneous administration of POM and oestradiol, a comparison of the kinetics of uptake on the uterus and of uterotrophic effects, as well as an analysis of radioactivity taken up by a partition method between petroleum ether and sodium hydroxide, indicates that cleavage of both ether groups of POM occurs leading to estradiol. It is likely that this de-etherification takes place in the liver after a period of quiescence. The lipophilic nature of POM allows an obvious uptake by the aorta and a very significant uptake by the adipose tissue. The etherification of the alcohol functions of oestradiol allows an adequate protection of the hormone against hepatic catabolism. This may explain, along with the release of metabolites taken up by the adipose tissue, that POM is bound to a greater extent than oestradiol by various tissues.
The incubation of PE2 ((6,7-3H)-labelled 3-propyl ether of estra-1,3,5(10)triene-3, 17 beta-diol (estradiol)) with various subcellular fractions of rat liver indicated that the hepatic metabolism of this compound occurs mainly in the microsomal fraction. In addition to the formation of 3-propyl ethers of estra-1,3,5(10)triene-3-ol-17-one (estrone) and estra-1,3,5(10-triene-3, 16alpha, 17 beta-triol (estriol) directly deriving from PE2, the microsomal proteins carried out the deetherification of the propyl ether group leading to phenolic steroids; among them, estradiol, estrone, and estriol were characterized. Protein-bound and water-soluble metabolites were found; the effects of glutathione and of the incubation conditions were in agreement with the thioconjugation of these derivatives. The microsomal metabolism of PE2, and specially the deetherification reaction, required the presence of oxygen and of NADPH as cofactor, the optimum pH ranging from 7.4 to 8. The participation of cytochrome P450 in these metabolic pathways was shown by a partially inhibited catabolism with carbon monoxide and by a more active metabolism in males than in females and when animals were pretreated with phenobarbital. These results allowed us to conclude that the hepatic deetherification of PE2 is carried out by a microsomal oxidative system which is very similar to the system involved in the demethylation of methyl ethers of estrogens.
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