Effects of flucinolone acetonide on mouse skin sterol metabolism and two-stage carcinogenesis

Abstract

Fluocinolone acetonide (FA) is one of the most potent synthetic glucocorticoids and is known to possess an anti-tumor promoting activity. An attempt was made to evaluate this activity by estimating tumor promoting activity. Unexpectedly, when 10 micrograms of FA was applied alone or after a single application of a subcarcinogenic dose of 3-methylcholanthrene to mouse skin, results suggested that FA itself may be a tumor promoter or a complete carcinogen. Other glucocorticoids tested, e.g. dexamethasone, hydrocortisone and prednisolone, also revealed similar effects but were less potent than FA. To verify the possibility that glucocorticoid is a complete carcinogen or a tumor promoter, a tumor incidence experiment was performed for 24 weeks. As a result it was found that FA possesses a tumor promoting activity at some dose levels but no tumor initiating activity.

Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity

“…Amongst these are glucocorticoids that promote Smo ciliary accumulation in the current study. Further, FA is reported to act as a tumor promoter in the skin(Fukao, et al, 1988). Our studies also raise the possibility of high dosing of glucocorticoids leading to off-target action of glucocorticoid agents in the Hh pathway, modifying therapeutic outcome: for example, in Hh-antagonist-directed cancer therapy.…”

Biosynthesis of Cholesterol and Other Sterols

“… 10 , 164 , 165 The second demethylation in which the latter C4α-sterol intermediate is converted into a 4-desmethyl sterol is mechanistically identical and is catalyzed by the same membrane-bound cytochrome b 5 pathway that participates in the electron carrier from NADPH to the demethylation complex. 10 , 166 , 167 …”

“…Recent study of cloned enzymes showed that the overall C4 demethylation process involves (i) the sequential reaction of C4α monohydroxylation of the 4,4-dimethyl substrate and oxidation of the CH 2 OH group to the carboxyl stage catalyzed by sterol C4α-methyl oxidase (4-SMO), (ii) oxidative decarboxylation by sterol C4α-decarboxylase (4-SDC) [also known as 3β-hydroxysteroid-dehydrogenase/C4-deacarboxylase, 3βHSD/D)] complexed with NAD + followed by tautomerism, and then (iii) stereospecific reduction by a NAD(P)H-dependent sterone reductase of the 4-monomethyl-3-ketone to the 4-monomethyl-3β-alcohol catalyzed by sterol 3-reductase (3-SR). ,, The second demethylation in which the latter C4α-sterol intermediate is converted into a 4-desmethyl sterol is mechanistically identical and is catalyzed by the same membrane-bound cytochrome b 5 pathway that participates in the electron carrier from NADPH to the demethylation complex. ,, …”

“…Sterol research changed in the mid- to late 20th century and centered on biomimetic chemistry, tracer work, enzymology, and structure determination using high-field NMR and X-ray diffraction methods, culminating with a broad outline for cholesterol synthesis and the partial or complete purification of all the microsomal-bound enzymes that act on sterols between lanosterol and cholesterol. − Ergosterol, then cholesterol, was discovered to play multiple cellular roles associated with membrane (bulk role) and signal (sparking) functions, which could be differentiated by structure and amount of compound; − notably sterols accumulate in cultured plant and animal cells at approximately 3000 fg/cell and in yeast at 20 fg/cell . During this time, there was a renewed focus on regulation of cholesterol synthesis and human physiology .…”