Influence of subchronic administration of oestrone-3-O-sulphamate on oestrone sulphatase activity in liver, spleen and white blood cells of ovariectomized rats.
Inhibition of oestrone sulphatase followed by oestrogen removal from tumour cells may be a new form of endocrine therapy of breast cancer in women. We investigated the inhibitory effect of the subchronic administration of oestrone-3-O-sulphamate (EMATE), a steroid sulphatase inhibitor, to ovariectomized rats, to evaluate this method for testing new nonsteroidal inhibitors. EMATE in DMSO was administered both orally and subcutaneously (s.c.) for 7 days at doses of 0.5 and 2.5 mg/kg. In addition the rats were injected s.c. with 0.5 mg oestrone sulphate/kg 26 and 2 h before decapitation under ether anaesthesia. Oestrone sulphatase activity (ESA) was measured radiometrically using [3H]oestrone sulphate as substrate for desulphuration in white blood cells, liver homogenate, microsomes and spleen homogenate. ESA in liver microsomes was found to be nearly 40 times higher than in white blood cells while in spleen ESA was nearly half of that found in liver homogenates and white blood cells. ESA can be inhibited by EMATE down to 50-1.5% of control activity depending on the dose and administration route. The inhibition was in the order, liver homogenate < spleen < liver microsomes < white blood cells, and was more pronounced after s.c. administration of the inhibitor than after oral administration. Ovariectomy was found to be not necessary for oestrone sulphatase-inhibiting studies. Two sequential s.c. injections of oestrone sulphate enhanced the enzyme activities significantly in liver and white blood cells, but not in spleen. In conclusion, white blood cells and liver microsomes of intact female rats can be used for ESA-inhibiting studies. Sulphate-conjugated oestrone can induce oestrone sulphatase in vivo in liver and white blood cells thereby enhancing oestrogen supply in the peripheral organs.
Barth
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A
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany. ABAR@mti-n.uni-jena.de
Römer
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Oettel
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D000284:Administration, Oral; D000818:Animals; D021461:Animals, Outbred Strains; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D004970:Estrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D005260:Female; D007279:Injections, Subcutaneous; D007962:Leukocytes / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects* / Q000201:enzymology; D013429:Sulfatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018675:Toxicity Tests; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D004791:Enzyme Inhibitors; C088768:estrone-3-O-sulfamate; D004970:Estrone; D013429:Sulfatases; C020121:estrone sulfatase