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Title: The metabolism of drugs and steroids in the placenta
Author: Hopkins, Robert
ISNI:       0000 0001 3581 5400
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1973
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The present investigations were primarily aimed at defining the detoxicating capacity of the placenta, and then to a more general study of steroid and fatty acid metabolism. Concomitant studies were undertaken with foetal and maternal liver, plus certain other steroidogenic organs. Cytochrome P-450 was demonstrated both in the mitochondrial and microsomal fractions of human and rabbit placentae, but associated only with the microsomes in rat placenta. Evidence for rat and ferret testicular cytochrome P-450 has been presented. The placental CO-binding pigment responded similarly to that of maternal liver with regard to storage, deoxycholate treatment and the capacity of the reduced pigment to bind metyrapone. It did not prove possible to elicit binding spectra with various endogenous and foreign substrates normally metabolized by the hepatic microsomal mixed function oxidase system. Whereas enzyme inducing agents elevated foetal and maternal hepatic cytochrome P-450, they did not significantly alter such levels in the placenta. The ability of placentae from humans, rats, rabbits and pigs to metabolize a variety of anutrients, including hydroxylation of biphenyl, benzo[a]pyrene and zoxazolamine, N-demethylation of ethylmorphine and p-chloro-N-methylaniline, O-demethylation of p-nitroanisole, reduction of p-nitrobenzoic acid, hydrolysis of phenolphthalein glucuronide and conjugation of 4-methylumbelliferone, was examined. This activity was either not detectable or present at a rate no greater than 30% of that maternal liver (excluding B-glucuronidase activity). Foetal liver and certain steroidogenic organs studied exhibited comparable drug-metabolizing activity to that of placenta. The routes of detoxication in the placenta were usually distinct from those of maternal liver, and were not mediated through cytochrome P-450. Pretreatment of pregnant animals with enzyme inducing agents resulted in a proliferation of endoplasmic reticulum and drug-metabolizing activity of the maternal liver, but in the placenta the response was comparatively very small. The detoxicating capacity of the maternal liver did not appear markedly reduced during pregnancy. Unlike placentae of rats and rabbits, those of humans and pigs demonstrated a steroid ring-A aromatizing system involved in oestrogen biosynthesis. In the human placenta, the activity was largely associated with the microsomes. Nicotinamide was required in the homogenizing media for optimal activity, and in certain cases there was a need for Mg[++]. The multienzyme complex proved resistant to solubilization by treatment with deoxycholate, Triton WR-1339, papain, lipase and sonication. No inhibition of activity was observed in the presence of up to 90% CO with O[2] maintained at 5%. The studies strongly indicated that the steroid ring-A aromatizating system studied in the placenta was not mediated by a cytochrome P-450 mixed function oxidase system. Incubations in the presence of a variety of steroids, fatty acids and xenobiotics characterized the enzymes involved. The placentae of rats, rabbits and humans were found not to o-hydroxylate lauric acid, unlike the enzyme system of liver which is capable of oxygenating drugs and steroids also.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available