Green J L, Pan Y H, Reed G A
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Carcinogenesis. 1991 Jul;12(7):1359-62. doi: 10.1093/carcin/12.7.1359.
The interaction between the sulfite anion and specific benzo[a]pyrene (B[a]P) derivatives produces a novel class of benzo[a]pyrene sulfonates. (+/-)-7,8,9-Trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-10-sulfonate (B[a]PT-10-sulfonate) is formed in high yields in incubations containing (+/-)-7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyre ne (anti-BPDE) and sulfite, and sulfite strongly enhances the mutagenicity of the diolepoxide toward Salmonella typhimurium under those conditions. Although B[a]PT-10-sulfonate itself shows little direct mutagenicity over a 1-20 microM concentration range, this reactive bay-region intermediate does enhance the mutagenicity of anti-BPDE in strains TA98 and TA100 by up to 280%. No significant enhancement was seen when up to 20 microM B[a]PT-10-sulfonate was used in concert with another direct-acting mutagen, N-acetoxy-acetylaminofluorene (N-AcO-AAF). The isomeric product derived from sulfite and (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol) is (+/-)-7,8,10-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-9-sulfonate (B[a]PT-9-sulfonate). Like B[a]PT-10-sulfonate, B[a]PT-9-sulfonate is not mutagenic to strains TA97, TA98 and TA100. This sulfonate exhibited little enhancing activity with anti-BPDE over a 1-20 microM concentration range, but did enhance the mutagenic response of strain TA98 to 0.2 microM N-Aco-AAF by up to 128%. Sulfite, anti-BPDE and B[a]PT-sulfonates were also examined for the ability to induce a forward mutation at the hgprt locus (8-azaguanine resistance) in strains of S.typhimurium. Sulfite caused a marked enhancement of forward mutation due to anti-BPDE in both TA98 and TA100. Surprisingly, concurrent administration of B[a]PT-10-sulfonate with anti-BPDE did not increase the number of mutant colonies. The extensive conversion of anti-BPDE to B[a]PT-10-sulfonate under conditions where sulfite enhances diolepoxide mutagenicity, when coupled with this enhancement of diolepoxide mutagenicity by B[a]PT-10-sulfonate in the reverse mutation assay, supports this novel B[a]P derivative as a mediator of the sulfite-dependent enhancement of B[a]P genotoxicity. Determining why this enhancing effect was not seen when selecting for mutation at the hgprt locus of S.typhimurium will require further study.
亚硫酸根阴离子与特定的苯并[a]芘（B[a]P）衍生物之间的相互作用产生了一类新型的苯并[a]芘磺酸盐。在含有（±）-7r,8t-二羟基-9t,10t-环氧-7,8,9,10-四氢苯并[a]芘（反式-BPDE）和亚硫酸盐的孵育体系中，（±）-7,8,9-三羟基-7,8,9,10-四氢苯并[a]芘-10-磺酸盐（B[a]PT-10-磺酸盐）能以高产率形成，并且在这些条件下，亚硫酸盐能显著增强二环氧物对鼠伤寒沙门氏菌的致突变性。尽管在1 - 20微摩尔浓度范围内，B[a]PT-10-磺酸盐本身几乎没有直接致突变性，但这种具有反应活性的湾区中间体确实能使反式-BPDE在TA98和TA100菌株中的致突变性增强高达280%。当高达20微摩尔的B[a]PT-10-磺酸盐与另一种直接作用的诱变剂N-乙酰氧基-乙酰氨基芴（N-AcO-AAF）联合使用时，未观察到显著增强作用。由亚硫酸盐和（±）-7,8-二羟基-7,8-二氢苯并[a]芘（B[a]P-7,8-二醇）生成的异构体产物是（±）-7,8,10-三羟基-7,8,9,10-四氢苯并[a]芘-9-磺酸盐（B[a]PT-9-磺酸盐）。与B[a]PT-10-磺酸盐一样，B[a]PT-9-磺酸盐对TA97、TA98和TA100菌株没有致突变性。在1 - 20微摩尔浓度范围内，这种磺酸盐对反式-BPDE几乎没有增强活性，但确实能使TA98菌株对0.2微摩尔N-Aco-AAF的致突变反应增强高达128%。还检测了亚硫酸盐、反式-BPDE和B[a]PT-磺酸盐在鼠伤寒沙门氏菌菌株中诱导次黄嘌呤-鸟嘌呤磷酸核糖转移酶（hgprt）位点正向突变（8-氮杂鸟嘌呤抗性）的能力。亚硫酸盐能使TA98和TA100中由反式-BPDE引起的正向突变显著增强。令人惊讶的是，将B[a]PT-10-磺酸盐与反式-BPDE同时给药并没有增加突变菌落的数量。在亚硫酸盐增强二环氧物致突变性的条件下，反式-BPDE大量转化为B[a]PT-10-磺酸盐，再加上在回复突变试验中B[a]PT-10-磺酸盐对二环氧物致突变性的这种增强作用，支持了这种新型B[a]P衍生物作为亚硫酸盐依赖性增强B[a]P遗传毒性的介质。要确定在选择鼠伤寒沙门氏菌hgprt位点突变时为何未观察到这种增强作用，还需要进一步研究。
