1. Hydroxylation activities toward steroid hormones were determined for eleven forms of human hepatic cytochrome P450s expressed in yeast Saccharomyces cerevisiae cells. Microsomes were prepared from the yeast cells and assayed for their regioselectivity of hydroxylation toward progesterone, pregnenolone, dehydroepiandrosterone (DHEA) and oestrone. 2. 6 beta-Hydroxylation of progesterone was catalysed most efficiently by CYP3A4, followed by CYP2D6. CYP3A4 showed the highest progesterone 16 alpha-hydroxylation activity, followed by CYP1A1 and CYP2D6. 16 alpha-Hydroxylation of pregnenolone was catalysed efficiently by CYP1A1 and CYP3A4. Only CYP3A4 exhibited 16 alpha-hydroxylase activities toward DHEA and oestrone. 3. Addition of nifedipine, a typical substrate of CYP3A4, inhibited the 6 beta- and 16 alpha-hydroxylation of progesterone by CYP3A4. 4. These results suggest that CYP3A4 and CYP1A1 are responsible for the hydroxylation of these endogenous steroids, as well as xenobiotics, in human liver.
Urinary cortisol metabolites are altered both quantitatively and qualitatively in thyroid dysfunction. This study was conducted to elucidate the usefulness of urinary cortisol metabolites in the assessment of peripheral thyroid hormone action, particularly in the patients with inappropriate thyrotropin secretion. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) level and gas chromatographical steroid profile were studied in 25 hyperthyroid, 18 hypothyroid, and 24 euthyroid control subjects. Five patients with generalized thyroid hormone resistance and two patients with thyrotropin secreting pituitary tumor were also studied. The ratio of urinary tetrahydrocortisone to tetrahydrocortisol (THE/THF) was significantly elevated in hyperthyroidism (4.58 +/- 1.49) and depressed in hypothyroidism (1.31 +/- 0.55) compared to control (1.93 +/- 0.35). There were good correlations between THE/THF and serum thyroid hormone levels, especially in hypothyroidism. THE/THF can be a good biochemical indicator for deficiency of peripheral thyroid hormone action. Two patients with thyrotropin-secreting tumor showed high THE/THF, which reflected thyroid hormone excess. In contrast, THE/THF in the patients with generalized thyroid hormone resistance was low as compared to high serum thyroid hormone levels. Similar findings were demonstrated with 17-OHCS but discrimination of thyroid hormone resistance was insufficient. Thus, the ratio of the urinary concentrations of cortisol metabolites, THE/THF, appears to be a good marker for peripheral thyroid hormone resistance.
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