Effect of chemical carcinogens on cholesterol biosynthetic pathways in the skin of mice.
The metabolism of zymosterol and mevalonic acid was studied in vitro using the skin homogenates of 3-methylcholanthrene (3MC), diazacholesterol-treated and untreated mice. In normal mouse skin only lathosterol was a major metabolite and the other metabolites, cholesta-5,7,24-trien-3 beta-ol, desmosterol, cholesterol and 7-dehydrocholesterol were much less abundant. However, in the skin homogenate of mice treated with 3MC lathosterol production was depressed, while the production of cholesta-5,7,24-trien-3 beta-ol and desmosterol was significantly increased, the cholesterol level being normal or a little higher. In contrast, in the skin homogenate of mice administered diazacholesterol the production of both lathosterol and cholesterol was almost completely blocked with the slightly increased production of cholesta-5,7,24-trien-3 beta-ol and desmosterol. The metabolism in vitro of [2-14C]-mevalonic acid was quite similar to that of zymosterol, and no additional product which might possibly have been produced by the Kandutsch-Russell pathway was observed. Two pathways for cholesterol biosynthesis, therefore, may exist in mouse skin; the first is lanosterol----zymosterol----5 alpha-cholesta-7,24-dien-3 beta-ol----lathosterol----7-dehydrocholesterol----cholesterol, and the second by Bloch: lanosterol----zymosterol----5 alpha-cholesta-7,24-dien-3 beta-ol----cholesta-5,7,24-trien-3 beta-ol----desmosterol----cholesterol. When mouse skin is treated with 3-MC the former pathway is virtually blocked and the latter is stimulated, keeping the level of cholesterol in the tissue constant or a little higher than normal, which seems to be a significant change in the early stage of chemical carcinogenesis.
Department of Oral and Maxillofacial Surgery I, Hiroshima University, School of Dentistry, Japan.
Y
Y
Tanimoto
K
K
Fukao
K
K
Yoshiga
K
K
Takada
Y
Y
Ohyama
K
K
Okuda
D000818:Animals; D001373:Azacosterol / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D011865:Radioisotope Dilution Technique; D012016:Reference Values; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism; D014316:Tritium
D002273:Carcinogens; D013261:Sterols; D014316:Tritium; D008748:Methylcholanthrene; D002784:Cholesterol; D001373:Azacosterol; C015582:zymosterol; D008798:Mevalonic Acid