Effects of Glucocorticoids on Deoxyribonucleic Acid (DNA) Synthesis Stimulated by Growth Factors in Cultured Rat Skin Fibroblasts
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概要
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The effects of glucocorticoids on deoxyribonucleic acid (DNA) synthesis were studied by using confluent cultured rat skin fibroblasts prepared by enzymatic dispersion and expanded up to passage 3. Dexamethasone caused the inhibition of the DNA synthesis stimulated by 10% fetal calf serum (FCS) in a dose dependent manner. Maximum inhibition (90%-100%) was achieved by the concentration of 10^<-7>M. A similar dose dependent inhibition was also obtained in the experiment using epidermal growth factor (EGF) (1ng/ml) as a stimulant. Dexamethazone (10^<-7>M) also inhibited the DNA synthesis stimulated by somatomedin C (100ng/ml) or platelet derived growth factor (1 half-maximum unit/ml) almost to control levels. Binding studies with ^<125>I-labeled EGF suggested that dexamethasone caused this ihibitory action without modulation of cell surface receptors for EGF.Furthermore, the effects of a variety of glucocorticoids on the DNA synthesis were studied to clarify the structural requirement of glucocorticoids for the inhibition of the DNA synthesis. The results showed that 11β-hydroxyl and 21-hydroxyl groups on the steroid nucleus were necessary for the inhibition of the growth factor-stimulated DNA synthesis. Meanwhile, the inhibitory action on the DNA synthesis was markedly diminished by the replacement of a 16α-methyl group by a 16β-methyl group in the presence of a bulky group at C-17 (e.g. 17α-valerate). For further elucidation of mechanisms of action of glucocorticoids on the inhibition of the growth factor-stimulated DNA synthesis, the relationships between the structural features of glucocorticoids and their binding ability to the glucocorticoid receptor ([^3H]-dexamethasone-binding receptor) were studied. In most steroids (e.g. triamcinolone acetonide, betamethasone and hydrocortisone), the degree of the inhibition of DNA synthesis was almost correlated with the binding ability. But some steroids (e.g. progesterone, 11-deoxycorticosterone and betamethasone 17-valerate) which possesed no, or little, inhibitory action on the stimulated DNA synthesis showed a significant, or high binding, ability to glucocorticoid receptors. These results suggest that there are at least two kinds of structural requirement s for the inhibitory action of glucocorticoids on DNA synthesis, namely at the stage of receptor binding and the stage of post-receptor binding events.
- 公益社団法人日本薬学会の論文
- 1990-06-25
著者
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内田 恵理子
国立医薬品食品衛生研究所遺伝子細胞医薬部
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早川 尭夫
国立医薬品食品衛生研究所
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内田 恵理子
国立衛研
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内田 恵理子
National Institute of Hygienic Sciences
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早川 堯夫
National Institute of Hygienic Sciences
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早川 堯夫
国立医薬品食品衛生研究所生物薬品部
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田中 彰
National Institute of Hygienic Sciences
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Tanaka A
Faculty Of Pharmaceutical Sciences Tokyo University Of Science
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新見 伸吾
国立衛試・生物
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田中 彰
Division Of Biological Chemistry And Biologicals National Institute Of Health Sciences(present Addre
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新見 伸吾
National Institute of Hygienic Sciences
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早川 尭夫
Division Of Biological Chemistry And Reference Standards National Institute Of Hygienic Sciences
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Uchida Eriko
Human Genome Center Institute Of Medical Science University Of Tokyo
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