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

Authors:
  • KFKen-Ichi Fukao
    Ken-Ichi Fukao
  • KYKoji Yoshiga
    Koji Yoshiga
  • KTKazuaki Takada
    Kazuaki Takada
  • YOYoshihiko Ohyama
    Yoshihiko Ohyama
  • KOKyuichiro Okuda
    Kyuichiro Okuda
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Abstract
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-dehydrocholestrol 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 diazacholestrol 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 .fwdarw. zymosterol .fwdarw. 5.alpha.-cholesta-7,24-dien-3.beta.-ol .fwdarw. lathosterol .fwdarw. 7-dehydrocholesterol .fwdarw. cholesterol, and the second by Bloch: lanosterol .fwdarw. zymosterol .fwdarw. 5.alpha.-cholesta-7,24-dien-3.beta.-ol .fwdarw. cholesta-5,7,24-trien-3.beta.-ol .fwdarw. desmosterol .fwdarw. 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.

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