Pharmacological Reviews, Vol 13, 329-359, Copyright © 1961 by the American Society for Pharmacology and Experimental Therapeutics

HEPATIC AND EXTRAHEPATIC REGULATION OF CORTICOSTEROIDS

¹ Department of Anatomy, University of Utah College of Medicine, Salt Lake City, Utah

It appears from a review of the work of numerous authors that cells of many types, including mammalian and bacterial cells, can metabolize steroid hormones. Different cells of the mammal have quantitatively and qualitatively different

capacities to perform steroid metabolism. Biosynthesis of steroids appears at present to be an exclusive property of cells derived from the genital ridge. The steroid hormones, once synthesized, have two fates. The first is that the substituted groups of the steroid nucleus are oxidized or reduced to form other steroid molecules. Some of these metabolites possess known functions. In the process of conversion, however, the transformed steroid usually loses, either quantitatively or qualitatively, its original biological activity but may acquire a different function. The conversion of one steroid hormone to another by peripheral cells other than those capable of biosynthesis has been called biotransformation. A second fate is the conjugation of steroid metabolites which can then be excreted.

Many peripheral cells perform the first type of metabolic transformation, but only the liver has been shown so far to be able to form tetrahydrocorticosteroids, which is an essential step before conjugation. The kidney can conjugate corticosteroids provided they are already in the tetrahydro form. The oxidation and reduction of steroid molecules (biotransformation) may be reversible or irreversible. The degree of reversibility thus regulates partly the necessity for replenishing the supply of the steroid hormone.

The concept of active and inactive steroid hormones is used to indicate the presence or absence of a particular biological activity which is dependent upon the presence or absence of certain substituent groups on the steroid nucleus.

Prevention of oxidation or reduction of the steroid hormone keeps it in the active state, since the original structure-activity relation is maintained. It appears, although it has not been proved in each case, that increased potency of synthetic steroid hormones is due in part to the fact that essential positions for activity are protected from normal metabolism. The point of view presented here is that the actual mechanism of action for most if not all steroid hormones is still not understood and that the metabolism of these hormones is related not to mechanism of action but to their turnover, which imposes requirements for steroid renewal.

Non-steroidal hormones which influence steroid hormone biosynthesis, such as pituitary hormones, also directly influence steroid metabolism. Other hormones may influence steroid hormone metabolism by more indirect meansincreasing their biosynthesis, biotransformation and conjugation, and excretion. The major emphasis in this review has been upon the steroid metabolism of lymphocytes, fibroblasts, reticuloendothelial cells, hepatocytes, and their malignant counterparts. These cells appear to be among the most important target cells for corticosteroid activity.

Recent findings indicate that biological activity exists for metabolites which were thought to be inactive. Other metabolites may possess important functions which are at present unknown. The concept of biotransformation may have future practical and scientific importance because it may be possible to control the production of particular metabolites and thus control certain biological responses. For example, testosterone, an androgenic hormone, can he transformed to pyrogenic or hypocholesterolemic steroids. Estrogens seem to favor

the formation of the metabolite which has hypocholesterolemic effect. It is possible that thyroid hormone might have a similar effect. The control of the preferential production of the pyrogenic steroid has not been investigated. In the opinions of the reviewers, the implications of this field of steroid hormone research for a further understanding of physiological and pathological processes are enormous.

The importance of abnormal metabolism by malignant cells may lead to new points of view concerning the fundamental processes of malignant growth and are already important in the diagnosis of some malignancies. Further research along this line offers rational avenues to the development of new steroid hormones for treatment of some types of cancer.

Note:

The authors wish to thank Dr. Alejandro Zaffaroni, Dr. Bernard I. Grosser, and Dr. George H. Acheson for their constructive comments and criticisms of this review.