Induction of steroid glucuronyltransferase and repression of hydroxysteroid oxidoreductase: Recent findings

Abstract

Steroid hormones are excreted mainly as glucuronides. Malfunction or deficiency of the enzyme which glucuronidates steroid hormones (UDP-glucuronate-17β-oestradiol 3-glucuronyltransferase) is relatively rare. On the other hand, several studies have shown that the enzyme is inducible. One major objection to these induction studies is that they have been carried out with nonphysiological substrates. Therefore, the kinetics and physicochemical properties of the enzyme from various sources have now been investigated using physiological substrates. In view of the extensive use of steroid hormones in medicine, it was important to know whether steroid glucuronyltransferases are induced by their own substrates. The results showed that ovariectomy leads to a 56% decrease in oestrone glucuronyltransferase activity. Administration of oestradiol-17β to rats induced the enzyme to normal activity after 12 days; after 15 days, the activity was twice the control value. Actinomycin d and cycloheximide blocked the oestradiol-17β-induced increase in enzyme activity. These results provide strong evidence that oestrogen glucuronyltransferase is induced by its substrate. It is well established that hydroxysteroid oxidoreductases (HSOR) play a major role in the intermediary metabolism of androgens and oestrogens. Previously, it was shown that the activity of the 17β-HSOR, catalysing the oxidoreduction of oestradiol-17β and oestrone in rat liver, is different in female and male animals. When female animals were gonadectomised, the time course of development of enzyme activity was almost identical to that observed in male rats. This finding indicated that the female hormone may have a repressive effect on the activity of the 17β-HSOR in adult rats. Further studies revealed that isoenzymes exist in the cytosol fraction, two of which show a clear dependence on the hormonal status of the rat. With NAD as cofactor, the apparent Michaelis constant ( k m ) of the major 17β-HSOR from female rats was found to be 514 μmol/l, whereas the corresponding value for male rats was considerably lower at 58 μmol/l. With NADP as cofactor, the apparent k m values of the female and the male enzyme were similar. These results indicate that oestrogens regulate the activity of the soluble 17β-HSOR in liver by different mechanisms, including one where oestrogens have a “repressing” effect on enzyme synthesis.