Comparative mutagenicity of apicidin and apicidin derivatives (SD-0203 and SD-2007), histone deacetylase inhibitors.
The fungal metabolite apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)] is known to inhibit histone deacetylase (HDAC). In this study, the genotoxicity of apicidin and its derivatives were tested using three tests: a bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration (CA) test, and an in vivo micronucleus (MN) test. Apicidin was negative in the Ames test in the presence and absence of the microsomal metabolizing enzyme system. Apicidin induced a significant increase in the total chromosome aberrations in Chinese hamster ovary (CHO) cells. In the MN test, apicidin induced mutagenic activity at the highest dose (1000 microM/kg). The apicidin derivatives SD-0203 and SD-2007 did not induce mutagenic activity in the Ames test and no significant mutagenic potency was observed in the CA test. However, these compounds significantly and dose-dependently increased the number of micronucleated polychromatic erythrocytes (MNPCEs) as well as the PCE/(PCE + NCE) ratio in the MN test. These results suggest that apicidin and its derivatives preferentially induce CA and MN but are not effective in the Ames test.
Yoo
Eun J
EJ
Division of Toxicology, School of Pharmacy, SungKyunKwan University, Suwon, Kyonggi-Do, South Korea.
Lee
Byung M
BM
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D016466:CHO Cells; D002869:Chromosome Aberrations / Q000139:chemically induced; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000633:toxicity; D056572:Histone Deacetylase Inhibitors; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D010456:Peptides, Cyclic / Q000633:toxicity*; D012485:Salmonella typhi / Q000187:drug effects / Q000235:genetics
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C506659:SD-0203; C506660:SD-2007; C102351:apicidin