Abstract
The duclauxin derivatives xenoclauxin and desacetylduclauxin were examined for their effects on the growth of L-1210 murine leukemia cells, on the induction of DNA repair in the rat and mouse hepatocyte primary culture (HPC/DNA repair test), and on oxidative phosphorylation in mitochondria from rat livers in comparison to duclauxin. Both derivatives inhibited the growth of L-1210 culture cells as strongly as duclauxin. Duclauxin derivatives were negative in the HPC/DNA repair test. Xenoclauxin exhibited a potent uncoupling effect accompanying a marked depression of state 3 respiration of mitochondria in a similar fashion to that of duclauxin. Desacetylduclauxin significantly inhibited the state 3 respiration without causing uncoupling of oxidative phosphorylation in mitochondria. These results strongly suggest that xenoclauxin and desacetylduclauxin fromPenicillium duclauxii are not genotoxic but are cytotoxic mainly due to their potent inhibition of ATP synthesis in mitochondria.
Similar content being viewed by others
Abbreviations
- DNP:
-
2,4-dinitrophenol
- ETP:
-
electron transport particles
- HPC:
-
hepatocyte primary culture cells
- RC:
-
respiratory control
- TdR:
-
thymine deoxyribonucleotide
- UDS:
-
unscheduled DNA synthesis
References
CHANCE, B. AND WILLIAMS, G.R. (1955). Respiratory enzymes in oxidative phosphorylation I. Kinetics of oxygen utilization. J. Biol Chem.227:383–393.
FUSKA, J., KUHR, I., NEMEC, P., AND FUSKOVA, A. (1973). Antitumor antibiotics produced byPenicillium stipitatum. Thom. J. Antibiotics27:123–127.
HEYTLER, P.G. (1981). Uncouplers of oxidative phosphorylation inInhibitors of Mitochondrial Function (M. Erecinska AND D.F. Wilson, eds.) pp. 199–210. Pergamon Press, Oxford, New York, Toronto, Sydney, Paris.
KAWAI, K., NOZAWA, Y., KATO, T., AND YAMANAKA, N. (1982). Effects of xanthomegnin and duclauxin on culture cells of murine leukemia and Ehrlich ascitic tumor. Res. Commun. Chem. Pathol. Pharmacol.36: 429–438.
LARDY, H.A. (1981). Antibiotic inhibitors of mitochondrial energy transfer inInhibitors of Mitochondrial Function (M. Erecinska AND D.F. Wilson, eds.) pp. 187–198, Pergamon Press, Oxford, New York, Toronto, Sydney, Paris.
LOWRY, O.H., ROSENBROUGH, N.J., FARR, A.L., AND RANDALL, R.J. (1951). Protein measurement with Folin phenol reagent. J. Biol. Chem.193:265–275.
MORI, H., KAWAI, K., OHBAYASHI, F., KUNIYASU, T., YAMAZAKI, M., YAMAZAKI, M., AND WILLIAMS, G.M. (1984). Genotoxicity of a variety of mycotoxins in the hepatocyte primary culture/DNA repair test using rat and mouse hepatocytes. Cancer Res.44:2918–2923.
OGIHARA, Y., TANAKA, O., AND SHIBATTA, S. (1966). On the metabolites ofPenicillium duclauxii Delacroix III. The reaction of duclauxin with ammonia and primary amines. The structures of desacetylduclauxin, neoclauxin, xenoclauxin, and cryptoclauxin. Tetrahedron Lett.7:2867–2873.
PAPA, S., LOFRUMENTO, N.E., PARADIES, G., AND QUAGLIELLO, E. (1969). Mechanism of inhibition by uncouplers of succinate oxidation in isolated mitochondria. Biochim. Biophys. Acta180:35–44.
RUZICKA, H.J. AND CRANE, F. (1970). Quinone interaction with the respiratory chain-linked NADH dehydrogenase of beef heart mitochondria I. Juglone reductase activity. Biochim. Biophys. Acta233:71–85.
SHIBATA, S., OGIHARA, Y., TOKUTAKE, N., AND TANAKA, O. (1965). Duclauxin, a metabolite ofPenicillium duclauxii (Delacroix). Tetrahedron Lett.6:1287–1288.
SHIOJIRI, H., KAWAI, K., KATO, T., OGIHARA, Y., AND NOZAWA, Y. (1983). Cytotoxicities on culture cells and inhibitory effects on mitochondrial respiration of duclauxin and related compounds. Proc. Japan. Assoc. Mycotoxicol.18:38–41.
VAN DAM, K. (1967). The inhibitory effect on uncouplers of oxidative phosphorylation of mitochondrial respiration. Biochim. Biophys. Acta131 407–411.
WILLIAMS, G.M. (1976). Carcinogen-induced DNA repair in primary rat liver cell cultures: a possible screen for chemical carcinogens. Cancer Lett.1:231–236.
WILLIAMS, G.M. (1977). Detection of chemical carcinogens by unscheduled DNA synthesis in rat liver primary cell cultures. Cancer Res.37:1845–1851.
WILLIAMS, G.M. (1981). The detection of genotoxic chemicals in the hepatocyte primary culture/DNA repair tests. Gann Monogr. Cancer Res.27:45–55.
WILLIAMS, G.M., LASPIA, M.F., AND DUNKEL, V.C. (1982). Reliability of the hepatocyte primary culture/DNA repair test in testing of coded carcinogens and noncarcinogens. Mutat. Res.97:359–370.
WILSON, D.F. AND MERZ, R.D. (1967). Inhibition of mitochondrial respiration by uncouplers of oxidative phosphorylation. Arch. Biochem. Biophys.119:470–476.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kawai, K., Shiojiri, H., Nakamaru, T. et al. Cytotoxicity and genotoxicity of xenoclauxin and desacetyl duclauxin fromPenicillium Duclauxii (delacroix). Cell Biol Toxicol 1, 1–10 (1985). https://doi.org/10.1007/BF00717786
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00717786