Effect of chemical carcinogens on cholesterol biosynthetic pathways in the skin of mice

• Published in: Carcinogenesis (New York) 1990-09, Vol.11 (9), p.1647-1651
• Main Authors: Tanimoto, Yutaka, Fukao, Ken-ichi, Yoshiga, Koji, Takada, Kazuaki, Ohyama, Yoshihiko, Okuda, Kyuichiro
• Format: Article
• Language: English
• Subjects: Animals; Azacosterol - pharmacology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - pharmacology; Chemical agents; Cholesterol - analogs & derivatives; Cholesterol - biosynthesis; Male; Medical sciences; Methylcholanthrene - pharmacology; Mevalonic Acid - metabolism; Mice; Mice, Inbred ICR; Radioisotope Dilution Technique; Reference Values; Skin - drug effects; Skin - metabolism; Sterols - metabolism; Tritium; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/11.9.1647

The metabolism of zymosterol and mevalonic acid was studied in vitro using the skin homogenates of 3-methylcholanthrene (3MC), diazachotesterol-treated and untreated mice. In normal mouse skin only lathosterol was a major metabohte and the other metabolites, cholesta-5,7,24-trien-3β-ol, desmosterol, cholesterol and 7-dehydrocholesterol were much less abundant. However, in the skin homogenate of mice treated with 3MC lathosterot production was depressed, while the production of cholesta-5,7,24-tiien-3β-ol and desmosterol was significantly increased, the cholesterol levelbeing 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-3β-ol and desmosterol. The metabolism in vitro of [2−14C]-mevalonic acidwas 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 → 5α-cholesta-7,24-dien-3β-ol → lathosterol → 7-dehydro-cholesterol → cholesterol, and the second by Bloch: lanosterol → zymosterol → 5α-cholesta-7,24-dien-3β-ol → cholesta 5,7,24-trien-3β-ol → desmosterol → cholesterol. When moose 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.