Differential sensitivity of hepatic microsomal aryl hydrocarbon hydroxylase to the inhibitory effect of SKF 525-A in rats of varying age, hormonal- and drug-induced status

1982 ◽  
Vol 60 (8) ◽  
pp. 1083-1088 ◽  
Author(s):  
L. S. Gontovnick ◽  
G. D. Bellward
Keyword(s):  
Inhibitory Effect ◽  
Differential Sensitivity ◽  
Male Rats ◽  
Aryl Hydrocarbon Hydroxylase ◽  
Drug Induced ◽  
Adult Rats ◽  
Aryl Hydrocarbon ◽  
Hepatic Microsomes ◽  
Cytochrome P 450

The inhibition of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activity by SKF 525-A in vitro was studied in hepatic microsomes from rats of varying age, sex hormone status, and drug treatment. The concentration of SKF 525-A required to produce a 50% inhibition of AHH activity, the IC50, was determined for the various microsomal preparations. Microsomes from adult female and immature rats exhibited a similar sensitivity to SKF 525-A. However, microsomes from adult male rats were significantly more sensitive to the inhibitory effect of the drug. AHH activity from pseudohermaphroditic male rats was found to have the same sensitivity to SKF 525-A as in the female littermates. Microsomes obtained from adult rats that had been pretreated with various cytochrome P-450 inducing agents yielded significantly different IC50 values from untreated controls. These differences in IC50 values indicated that the predominant form(s) of cytochrome P-450 that hydroxylate benzo(a)pyrcne varied with the age, hormonal, and induced status of the animal.

Effect of chronic cysteamine treatment on mouse liver aryl hydrocarbon hydroxylase activity

1988 ◽  
Vol 66 (11) ◽  
pp. 1433-1436 ◽  
Author(s):  
Theresa C. Peterson
Keyword(s):  
Nephropathic Cystinosis ◽  
Aryl Hydrocarbon Hydroxylase ◽  
Serum Aminotransferase ◽  
Aryl Hydrocarbon ◽  
Human Dose ◽  
Aryl Hydrocarbon Hydroxylase Activity ◽  
In Vivo Effects ◽  
Cytochrome P 450

Patients receive chronic cysteamine in the management of nephropathic cystinosis. In a previous report our results indicated that acute cysteamine treatment inhibited cytochrome P-450. Cysteamine (85 mg/kg i.p.) was administered daily to female Swiss mice for 1.5 and 8.5 months. Cysteamine treatment (8.5 months) did not affect hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activity compared with controls. A small decrease in liver AHH activity was seen after 1.5 months of treatment with cysteamine. Liver histology, body weight, liver and spleen weights, and serum aminotransferase activity after chronic and subchronic treatment did not differ from controls. Chronic in vivo cysteamine treatment, unlike acute in vitro treatment did not decrease AHH activity. Incubation of isolated murine hepatocytes with cysteamine significantly inhibited AHH activity compared with controls. The inhibition occurred in a concentration-related manner, with 65% inhibition at 8.8 mM (1 mg/mL) (equivalent to the predicted plasma concentration using the maximally tolerable human dose), and 100% inhibition at 44 mM (5 mg/mL). The concentrations used in vitro were not cytotoxic. This suggests that chronic cysteamine treatment may not result in drug interactions and that in vitro results are not always good indicators of in vivo effects.

Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat

1996 ◽  
Vol 135 (4) ◽  
pp. 481-488 ◽  
Author(s):  
Antonio Torsello ◽  
Roberta Grilli ◽  
Marina Luoni ◽  
Margherita Guidi ◽  
Maria Cristina Ghigo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Mechanism Of Action ◽  
Direct Action ◽  
Male Rats ◽  
Surgical Ablation ◽  
Adult Rats ◽  
Gh Secretion ◽  
Plasma Gh

Torsello A, Grilli R, Luoni M, Guidi M, Ghigo MC, Wehrenberg WB, Deghenghi R, Müller EE, Locatelli V. Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat. Eur J Endocrinol 1996;135:481–8. ISSN 0804–4643 We have reported Hexarelin (HEXA), an analog of growth hormone-releasing peptide 6 (GHRP-6), potently stimulates growth hormone (GH) secretion in infant and adult rats. This study was undertaken to further investigate Hexarelin's mechanisms of action. In 10-day-old pups, treatments with HEXA (80 μg/kg, b.i.d.) for 3–10 days significantly enhanced, in a time-related fashion, the GH response to an acute HEXA challenge. Qualitatively similar effects were elicited in pups passively immunized against growth hormone-releasing hormone (GHRH) from birth. In adult male rats, a 5-day pretreatment with HEXA (150 μg/kg, b.i.d.) did not enhance the effect of the acute challenge, and the same pattern was present after a 5-day pretreatment in male rats with surgical ablation of the mediobasal hypothalamus (MBH-ablated rats). In addition, in adult sham-operated rats, Hexarelin (300 μg/kg, iv) induced a GH response greater (p < 0.05) than that induced by GHRH (2 μg/kg, iv). However, in MBH-ablated rats 7 days after surgery, GHRH was significantly (p < 0.05) more effective than HEXA, and 30 days after surgery HEXA and GHRH evoked similar rises of plasma GH. Finally, the in vitro Hexarelin (10−6 mol/l) effect was transient while GHRH (10−8 mol/l) induced a longer lasting and greater GH release. Three different mechanisms, not mutually exclusive, are postulated for Hexarelin stimulation of GH secretion in vivo: a direct action on the pituitary, though of minor relevance; an indirect action that involves release of GHRH, of relevance only in adult rats; and an action through the release of a still unknown hypothalamic "factor", which in infant and adult rats elicits GH release acting sinergistically with GHRH. Antonio Torsello, Department of Pharmacology, via Vanvitelli 32, 20129 Milano, Italy

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