azacosterol and lathosterol

Repeated topical application of 3-methylcholanthrene to the backs of BALB/c mice lowered the tissue levels of lathosterol and provitamin D3, intermediates in one of the cholesterol biosynthetic pathways (the delta 7 pathway), though the activities of lathosterol 5-desaturase and provitamin D3 7-reductase were similar to those of control animals. These results seemed to indicate that carcinogen treatment exerted a depressive effect at some earlier step(s) than lathosterol synthesis. However, the content of cholesterol in mouse skin was not lowered in these animals, suggesting that another biosynthetic pathway might be activated. When diazacholesterol, which is known to inhibit the conversion of desmosterol to cholesterol, was administered together with the carcinogen, a marked accumulation of desmosterol was observed compared to animals given only diazacholesterol. Since desmosterol is an intermediate in the pathway in which the delta 24 double bond is reduced at the final step (the delta 24 pathway), this seemed to suggest that the delta 24 pathway was activated by carcinogen treatment.

Topics: Administration, Topical; Animals; Azacosterol; Cholecalciferol; Cholesterol; Chromatography, Gas; Desmosterol; Female; Lanosterol; Methylcholanthrene; Mice; Mice, Inbred BALB C; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Skin

The effect of 20-methylcholanthrene and phorbol esters on sterol metabolism of mouse skin was studied. When 4 beta-phorbol esters were administered to mice that were previously painted once with 20-methylcholanthrene, a depression of some sterols in skin occurred, of which that of lathosterol was most marked. This effect was not observed when the order of application was reversed. Using a metabolic inhibitor, diazacholesterol, it was shown that sterols which reduce in mouse skin by administration of carcinogen and promoters were similar to those which reduce by administration of carcinogen only and are the members of one of the two cholesterol-biosynthetic pathways, i.e., a pathway which proceeds through intermediates with a saturated side chain. The intensity of the lathosterol-depressing effect of phorbol esters depends on the order of application of 20-methylcholanthrene and promoters, the amount of promoters, molecular species of alcoholic moiety of esters, and configuration at C-4 of phorbol moiety. Of the phorbol esters tested, 4 beta-phorbol-12-myristate-13-acetate revealed the highest activity, which was followed by 4 beta-phorbol-12,13-didecanoate, 4 beta-phorbol-12,13-dibutyrate, 4 beta-phorbol-12,13-dibenzoate, 4 beta-phorbol-12,13-diacetate, 4 alpha-phorbol-12,13-didecanoate, and 4 alpha-phorbol. 4 alpha-Phorbol was practically inactive. When beta-naphthoflavone was substituted for 20-methylcholanthrene, little effect was observed except in TPA, which revealed a rather marked lathosterol-depressing activity. Phorbol esters themselves did show some activity of lathosterol depression without prior application of 20-methylcholanthrene, but the effects were much weaker. When anthralin was applied to mouse skin after the painting of 20-methylcholanthrene, a low but definite lathosterol-depressing effect was observed.

Topics: Administration, Topical; Animals; Anthralin; Azacosterol; Benzoflavones; beta-Naphthoflavone; Cholesterol; Chromatography, Gas; Chromatography, Thin Layer; Male; Methylcholanthrene; Mice; Mice, Inbred ICR; Phorbol Esters; Phorbols; Skin; Sterols