Growth hormone regulation of hepatic drug-metabolising enzymes in humans and rats

Sammanfattning: There are pronounced sex-differences in the gene expression of several liver enzymes in the rat. The sex-differentiated secretion of growth hormone (GH) regulates these differences. We wanted to further investigate the mechanisms of this regulation in rats and to study the GH regulation of drug metabolism in man. The following clinical models where chosen a) GH deficient adult patients in need of long-term GH substitution and b) patients suffering from carcinoid syndrome intended for somatostatin analogue treatment. We studied the activities of three enzymes; cytochrome P450 (CYP) 3A, CYP2D6 and UDP-glucuronosyltransferase with codeine as probe drug.GH substitution gave a 66% increase of the CYP3A activity whereas the somatostatin analogues decreased this activity by 44%. This indicates that GH is involved in the regulation of CYP3A in man. Our findings may be of clinical importance when a GH-modulating drug or GH itself is combined with any of the numerous drugs metabolised by CYP3A. The changes in enzyme activity may also have endocrine consequences. A decrease in the CYP2D6 activity was also found during treatment with somatostatin analogues and may be due to other endocrine effects of the analogues.We studied the effect of one of the analogues, octreotide, on sex-differentiated enzymes in rats. Octreotide infusion "feminised" the gene expression or activity of two of the enzymes, probably as a result of a suppressed but "feminised" GH secretion pattern. We also studied the effects of Insulin-like growth factor I (IGF-I) on these enzymes and found that IGF-I feminised the expression of two of the enzymes. This indicates that IGF-I may be involved in the GH regulation of these enzymes.

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