ABSTRACT

The cytochrome P450 responsible for androgen synthesis by the placenta during the second half of pregnancy in the rat was studied in intact and hypophysectomized animals. The two activities of P450_17α, 17α-hydroxylase and C17,20-lyase, were limited to the junctional zone.

C17,20-Lyase activity was greater with progesterone than with 17-hydroxyprogesterone as substrate. Although the apparent Michaelis constants were similar, progesterone had a higher maximum velocity than 17-hydroxyprogesterone. Regardless of substrate, C17,20-lyase activity was greater with NADPH than with NADH as an electron donor, and there was no additive effect using both cofactors.

Administration of human chorionic gonadotrophin (hCG; 10IU at 09.00 and 21.00 h on days 13 and 14 and at 09.00 h on day 15) to intact females resulted in more than a 50% reduction of enzyme activity when measured on day 15. The same dose of hCG given to hypophysectomized animals with delayed implantation, i.e. pituitary removal on day 3 and implantation induced by oestrone 5 days later, had no effect on placental enzyme activity, but increased that in the ovary. Administration of ovine LH by osmotic minipump (days 11–15) to intact females resulted in abortion in all animals. The same treatment to animals hypophysectomized on day 11 produced abortion in three of four rats; enzyme activity was greatly reduced in the single animal with placentas. In contrast, infusion of LH into hypophysectomized animals with delayed implantation increased placental enzyme activities. However, administration of 20IU pregnant mare's serum gonadotrophin to the hypophysectomized animals on day 11 produced a large increase in ovarian follicular development and ovarian P450_17α activities, and resulted in abortion in three of five animals within 96 h.

The results indicate that the P450_17α of the junctional zone of the rat placenta has characteristics similar, if not identical, to those of the ovary with regard to preference of substrate and electron donor. However the enzyme activity in the placenta did not increase to the same extent as that in the ovary when exposed to gonadotrophins with LH activity, suggesting that the control mechanisms may be different.

Journal of Endocrinology (1990) 125, 217–224

Specific oestradiol binding to a receptor in nuclear and cytosol fractions of the rat anterior pituitary gland and pituitary responsiveness to gonadotrophin releasing hormone (GnRH) during the oestrous cycle have been studied. To accomplish this, both unoccupied and occupied oestradiol-binding sites in the cytosol and oestradiol-binding sites in the nucleus and total cell were measured during the oestrous cycle. The concentration of unoccupied and occupied sites and total oestradiol binding in the cytosol fluctuated during the cycle. At pro-oestrus, the concentration of cytosol receptor was diminished by about 40% and replenishment occurred during oestrus. On the other hand, a profound increase in concentrations of cellular and nuclear receptors occurred at pro-oestrus. Administration of GnRH significantly stimulated LH release at all stages of the cycle. The maximum stimulation of LH release by GnRH was observed at 13.00 h of pro-oestrus. From these studies, it is concluded that pituitary responsiveness to exogenous GnRH during pro-oestrus parallels the changes in the content of oestrogen receptors in the cytosol and nucleus.

Alendronate sodium, a primary amino bisphosphonate, is widely used in the treatment of various diseases that are associated with bone resorption, such as postmenopausal osteoporosis and Paget’s disease of bone. Although the adverse effects of biphosphonates on the gastrointestinal system have been demonstrated in experimental and clinical studies, the exact mechanisms underlying this damage are not clear yet. Ghrelin, a 28 amino acid peptide produced predominantly by the stomach, was shown to exert a potent protective action on the stomach of rats exposed to ethanol or stress.

Our objective was to evaluate the possible anti-oxidant and anti-inflammatory effects of ghrelin against alendronate-induced gastric damage. Wistar albino rats were administered alendronate (20 mg/kg) by gavage for 4 days, along with either ghrelin (10 ng/kg per day) or saline given i.p. After decapitation, stomach tissues were removed for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and tissue collagen content, while the extent of tissue damage was analyzed microscopically. Formation of reactive oxygen species was determined by chemiluminesence using a luminol probe in fresh gastric tissues. Serum tumor necrosis factor (TNF-α) and lactate dehydrogenase levels were assessed in trunk blood.

Oral administration of alendronate-induced significant gastric damage, accompanied by increased MPO activity, collagen content, MDA and luminol levels (P< 0.01–P< 0.001), while tissue GSH was decreased (P< 0.01). On the other hand, ghrelin treatment reversed these alterations (P< 0.05–P<0.001) as well as elevating serum TNF-α levels significantly (P< 0.001).

The findings of the present study suggest that alendronate induces oxidative gastric damage by a local irritant effect, and ghrelin ameliorates this damage by its possible antioxidant and anti-inflammatory properties.

The objective of this study was to examine the potential radioprotective properties of propylthiouracil (PTU)-induced hypothyroidism against oxidative organ damage induced by irradiation. Sprague–Dawley rats were pre-treated with saline or PTU (10 mg/kg i.p.) for 15 days, and were then exposed to whole-body irradiation (800 cGy). A group of rats were decapitated at 6 h after exposure to irradiation, while another group was followed for 72 h after irradiation, during which saline or PTU injections were repeated once daily. Lung, liver, kidney and ileum samples were obtained for the determination of malondialdehyde (MDA; an index of lipid peroxidation) and glutathione (GSH, an antioxidant) levels, myeloperoxidase activity (MPO; an index of tissue neutrophil accumulation) and collagen contents, while oxidant-induced DNA fragmentation was evaluated in the ileal tissues. All tissues were also examined microscopically and assayed for the production of reactive oxidants using chemiluminescence (CL). Lactate dehydrogenase (LDH), an indicator of tissue damage, and tumour necrosis factor-α (TNFα) were assayed in serum samples. Irradiation caused a significant decrease in GSH level, which was accompanied by significant increases in MDA levels, MPO activity, CL levels and collagen content of the tissues studied (P<0.05–0.001). Similarly, serum TNFα and LDH were elevated in the irradiated rats as compared with the control group. On the other hand, PTU treatment reversed all these biochemical indices, as well as histopathological alterations induced by irradiation. Our results suggested that PTU-induced hypothyroidism reduces oxidative damage in the lung, hepatic, renal and ileal tissues probably due to hypometabolism, which is associated with decreased production of reactive oxygen metabolites and enhancement of antioxidant mechanisms.