Programming and differentiation of rat liver enzymes

Abstract

At birth testicular androgens irreversibly programme hypothalamic centres involved in hypothalamopituitary control of hepatic sex-dependent steroid and drug metabolism. This imprinting process results in activation of a hypothalamic ‘feminostatin’—secreting centre that is turned on just before puberty. Feminostatin inhibits pituitary secretion of ‘feminotropin’, a novel pituitary hormone that feminizes the basal type of metabolism characterizing the autonomous liver, i.e. the liver of hypophysectomized and gonadectomized rats. Consequently, female rats that are devoid of feminostatin will secrete feminotropin from the pituitary, leading to a feminine type of hepatic metabolism. Male rats, on the other hand, have an active feminostatin-secreting centre and the inhibition of pituitary feminotropin release results in an autonomous type of liver metabolism. Full ‘masculinity’ of hepatic metabolism in male rats is induced by testicular androgens that act on the hypothalamo-pituitary axis to stimulate release of a pituitary ‘masculinizing factor’. Female rats show a relative androgen unresponsiveness and seem incapable of releasing masculinizing factor after treatment with androgens. A possible explanation for this is the absence of androgen receptor proteins in female brain as contrasted to the presence of androgen receptors in male pituitary, hypothalamus and pineal gland. It seems reasonable to assume on the basis of present knowledge that the level of androgen receptors in the central nervous system is programmed at the time of birth by testicular androgens.

The hypothesis presented above has been based on results obtained from experiments involving hypophysectomy, pituitary transplants under the kidney capsule, electrothermic lesions in the hypothalamus, neonatal and postpubertal castrations, treatment with androgens and estrogens at various times during development and transplantations with different lines of pituitary tumour cells. The novel pituitary hormone, feminotropin, has also been studied in vitro using hepatoma (HTC) cells or isolated hepatocytes in tissue culture. Feminotropin increases the apparent 5α-reductase activity in HTC cells at subsaturation concentrations of substrate (androstenedione) by decreasing the K_m value of the enzyme. Furthermore, feminotropin increases the apparent 5α/16α ratio in isolated hepatocytes, i.e. the ratio between total 5α-reduced and 16α-hydroxylated metabolites formed from androstenedione. Feminotropin has been shown to be different from any of the known pituitary hormones. It is stored in pituitary granules with a density of 1.13–1.17 g/cm³ and has a molecular weight of about 20,000 daltons. Feminotropin is produced by isolated pituitary cells in primary culture and by certain lines of pituitary tumour cells, e.g. C₈11RAP cells. Tissue culture medium from cultures of this cell line serves as source in our purification programme for feminotropin.