Shin M, Kim B, Mar W, Fang M, Son J, Kim M, Kwak H, Bae M, Byun T, Park S, Chun B, Byun J, An G, Lee B, Cho M
College of Veterinary Medicine, Seoul National University, Suwon, Korea.
Arzneimittelforschung. 2000 Mar;50(3):316-21. doi: 10.1055/s-0031-1300207.
This study was carried out to evaluate the mutagenic potential of recombinant antihemophilic factor VIII (GC-gamma AHF). Salmonella typhimurium (S. typhimurium) reversion assay with/without histidine moiety, chromosomal aberration assay on Chinese hamster lung (CHL) fibroblast cells and in vivo micronucleus assay using mouse bone marrow cells and supravital micronucleus assay using peripheral blood were performed. GC-gamma AHF containing histidine did show inconsistent and irregular mutagenic effects on S. typhimurium TA98, TA100, TA1535 and TA1537 both in the absence and presence of the metabolic activation system, however, GC-gamma AHF without histidine showed no mutagenic effects regardless of the metabolic activation system, thus suggesting that the histidine moiety in GC-gamma AHF might cause inconsistent mutagenic effect. Also GC-gamma AHF did not increase the number of cells having structural or numerical chromosome aberration in the cytogenetic test. In classical and supravital micronucleus assay, no significant increases were observed in the occurrence of micronucleated polychromatic erythrocytes and micronucleated peripheral lymphocytes in male ICR mice. These results strongly indicate that GC-gamma AHF has no genetic toxicity under these experimental conditions.
本研究旨在评估重组抗血友病因子VIII（GC-γ AHF）的致突变潜力。进行了含/不含组氨酸部分的鼠伤寒沙门氏菌回复突变试验、中国仓鼠肺（CHL）成纤维细胞的染色体畸变试验，以及使用小鼠骨髓细胞的体内微核试验和使用外周血的活体微核试验。含组氨酸的GC-γ AHF在代谢激活系统存在和不存在的情况下，对鼠伤寒沙门氏菌TA98、TA100、TA1535和TA1537均表现出不一致且不规则的致突变作用，然而，不含组氨酸的GC-γ AHF无论代谢激活系统如何均未显示致突变作用，因此表明GC-γ AHF中的组氨酸部分可能导致不一致的致突变效应。此外，在细胞遗传学试验中，GC-γ AHF并未增加具有结构或数量染色体畸变的细胞数量。在经典和活体微核试验中，雄性ICR小鼠的多染性红细胞微核化和外周淋巴细胞微核化发生率均未观察到显著增加。这些结果有力地表明，在这些实验条件下，GC-γ AHF没有遗传毒性。
