[Biosynthesis and microbial transformation of griseofulvin and carcinogenesis and prevention of cancer by estrogens].
In the biosynthetic study of griseofulvin by Penicillium urticae and microbial transformation of (-)- and (+)-dehydrogriseofulvin and their derivatives by Streptomyces cinereocrocatus excellent informations were obtained from 2H-NMR spectroscopy. In the reduction of (-)-dehydrogriseofulvin into (+)-griseofulvin by a partially purified enzyme system of S. cinereocrocatus, the origin of the 6' alpha-hydrogen of (+)-griseofulvin was a hydride ion donated by pro-4R-hydrogen of NADPH. In connection with the study of carcinogenesis, diethylstilbestrol (DES) was proved to disrupt microtubules in vitro. The other synthetic estrogens, E,E-dienestrol, meso-hexestrol, and dl-hexestrol were inhibitors of microtubule assembly in vitro, and induced twisted ribbon structures or ribbon-sheet-microtubules from microtubule proteins. Next, the effects of DES and its methyl ethers on the chromosome of and the cellular microtubule architecture, revealed by fluorescent anti-tubulin antibody, of Chinese hamster V79 cells were examined, and further estradiol-17 beta was proved to exhibit higher microtubule-disruptive activity than DES in V79 cells. Furthermore, cytoplasmic microtubules in the human breast cancer cell lines MCF-7 and MDA-MB-231, estrogen receptor-positive and -negative cell lines, respectively, were disrupted equally by estradiol-17 beta. Then, natural estrogens and their derivatives comprising 30 compounds in total were tested in Chinese hamster V79 cells, proving that 2-methoxyestradiol showed the strongest activity (EC50: 2 microM) to disrupt microtubules. Further, in the assay of indenestrol A, a metabolite of DES, indenestrol B and their monomethyl ethers, the 4'-methyl ether of [(-)-3S]-indenestrol B exhibited both the strongest cytotoxicity in, and greatest disruption of the cellular microtubules of V79 cells, and no correlation with the affinity for estrogen receptors was shown.
Sato
Y
Y
Kyoritsu College of Pharmacy, Tokyo, Japan.
D000077584:2-Methoxyestradiol; D000818:Animals; D006224:Cricetinae; D004958:Estradiol / Q000031:analogs & derivatives; D004967:Estrogens; D005260:Female; D006118:Griseofulvin / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D008868:Microtubule Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D009369:Neoplasms / Q000139:chemically induced*; D010407:Penicillium / Q000378:metabolism; D013302:Streptomyces / Q000378:metabolism
D004967:Estrogens; D008868:Microtubule Proteins; D006118:Griseofulvin; D004958:Estradiol; D000077584:2-Methoxyestradiol