Tayama S
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Mutat Res. 1996 Jul 5;368(3-4):249-60. doi: 10.1016/s0165-1218(96)90066-x.
Recently, hepatocarcinogenicity in rats and mice was reported with regard to the methylenedioxyphenyl compound, piperonyl butoxide (PB), which is used as a synergist for pyrethrins and related insecticides. Induction of sister-chromatid exchanges (SCEs) and chromosomal aberrations (CAs) due to PB were investigated using CHO-K1 cells with or without rat liver S9 fraction (S9); at the same time, the effects of safrole (SF), a methylenedioxyphenyl compound and a weak hepatocarcinogen, were also examined. PB (0.25 and 0.3 mM) and SF (0.8 mM) caused a slight but significant increase in SCEs followed by a cell-cycle delay in the 3-h treatment without S9. In the presence of S9 (4.5%), the cytotoxicity of PB or SF was weakened greatly or slightly, the top dose capable of cell division was raised to 0.6 mM (2-fold) or 1 mM, respectively. PB with S9 induced SCE at doses of 0.4 and 0.5 mM, and caused endoreduplications (ERDs, 7%) at a dose of 0.6 mM, while SF caused a dose-related significant increase in SCE at all doses used (0.4-1 mM) with S9. Genotoxicity of the metabolites of PB or SF was cleared by changing the dose of S9 (1.5-9%) while holding the dose of each chemical constant. In the case of SF (0.6 mM), induction of SCE, ERD and cell-cycle delay intensified almost in a dose-effect relationship, and CAs and a high level of ERD (14%) were caused by a 9% dose of S9. The concentration of unchanged SF in the incubated medium was certainly in inverse proportion to the dose of S9. This strongly suggests that the metabolites of SF are genotoxic. In the case of PB (0.3 mM), no positive responses were produced in the cultures, even with a high level of S9, though the amount of unchanged PB left in the incubated medium was very slight. This indicates that the metabolites of PB may not be genotoxic. In conclusion, PB and SF are possible to somewhat induce SCE at high dose(s) in the absence of S9, and the genotoxic effects of SF are more intensified in the presence of S9 than in its absence, while PB is probably no genotoxic in the presence of sufficient metabolic activation.
最近，有报道称，用作除虫菊酯及相关杀虫剂增效剂的亚甲二氧基苯基化合物胡椒基丁醚（PB）对大鼠和小鼠具有肝癌致癌性。使用有或没有大鼠肝脏S9组分（S9）的CHO-K1细胞，研究了PB引起的姐妹染色单体交换（SCE）和染色体畸变（CA）；同时，还检测了亚甲二氧基苯基化合物、弱肝癌致癌物黄樟素（SF）的作用。在无S9的3小时处理中，PB（0.25和0.3 mM）和SF（0.8 mM）导致SCE略有但显著增加，随后出现细胞周期延迟。在有S9（4.5%）存在的情况下，PB或SF的细胞毒性大大减弱或略有减弱，能够进行细胞分裂的最高剂量分别提高到0.6 mM（2倍）或1 mM。有S9时，PB在0.4和0.5 mM剂量下诱导SCE，并在0.6 mM剂量下导致核内复制（ERD，7%），而SF在所有使用剂量（0.4 - 1 mM）下与S9一起导致SCE呈剂量相关的显著增加。在保持每种化学物质剂量不变的情况下，通过改变S9的剂量（1.5 - 9%），清除了PB或SF代谢产物的遗传毒性。对于SF（0.6 mM），SCE、ERD的诱导和细胞周期延迟几乎呈剂量效应关系增强，9%剂量的S9导致CA和高水平的ERD（14%）。孵育培养基中未变化的SF浓度肯定与S9的剂量成反比。这强烈表明SF的代谢产物具有遗传毒性。对于PB（0.3 mM），即使使用高水平的S9，培养物中也未产生阳性反应，尽管孵育培养基中残留的未变化PB量非常少。这表明PB的代谢产物可能没有遗传毒性。总之，PB和SF在无S9时高剂量下可能会在一定程度上诱导SCE，并且S9存在时SF的遗传毒性作用比不存在时更强，而在有足够代谢激活的情况下PB可能没有遗传毒性。
