Modulatory effects of polycyclic aromatic hydrocarbons on the mutagenicity of 1-nitropyrene: a structure-activity relationship study.
Benzo[a]pyrene (B[a]P) is able to inhibit the mutagenicity of 1-nitropyrene (1-NP) through the reduction of nitroreductase activity and formation of adducts with DNA. The relationships between the chemical structure of 9 polycyclic aromatic hydrocarbons (PAHs) and antagonistic effects on the 1-NP-induced mutation were evaluated by the binary mixtures of 1-NP and PAHs with Salmonella typhimurium TA98 in the absence of S9 mix. Remarkably different antagonistic effects of 9 PAHs on the mutagenicity of 1-NP were observed. Among the tested PAHs, coronene demonstrates the most antagonistic potential followed by benzo[g,h,i]perylene (B[g,h,i]P), benzo[e]pyrene (B[e]P), dibenzo[a,h]pyrene (DB[a,h]P), benzo[a]pyrene (B[a]P) and pyrene. Naphthalene, anthracene, and chrysene had only minor inhibitory activity on the 1-NP mutagenicity. The modifying effects of PAHs on the nitroreductase activity of TA98 strains in the presence of 1-NP were further examined from the production of 1-AP. The statistical analytical data showed that the inhibitory effect of PAHs on the mutagenicity of 1-NP significantly correlated with their effects on the nitroreductase activity (r = -0.69, p < 0.05). In addition, the formation of 1-NP-DNA adducts of the binary mixtures of 1-NP and PAH was determined by the 32P-postlabeling method. The results indicated that the modulatory effects of PAHs on the formation of 1-NP-DNA adducts were correlated well with their antagonistic activity (r = -0.91, P < 0.01). From the above results, the relationships between the chemical structure of PAHs and the antagonistic effects on the 1-NP mutagenicity were revealed by the surface area and electronic parameters of PAHs. The planar molecular area of PAHs was more convincingly correlated with the antagonistic effect on the mutagenicity of 1-NP (r = -0.81, p < 0.01) than that with the difference in energy, delta E, between EHOMO and ELUMO (r = 0.69, p < 0.05). According to the above, two possible mechanisms are involved in the interactive effect of the binary mixtures: (1) a higher binding affinity with nitroreductase for PAHs having a large planar surface area; and (2) a high energy of interaction between 1-NP and PAHs with a low delta E might decrease the nitroreductive capability.
Cherng
S H
SH
Environmental Toxicological Center, Chung Shan Medical and Dental College, Taichung, Taiwan, ROC.
Lin
S T
ST
Lee
H
H
D016587:Antimutagenic Agents / Q000494:pharmacology*; D001345:Autoradiography; D018736:DNA Adducts / Q000378:metabolism*; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009601:Nitroreductases / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000494:pharmacology*; D011721:Pyrenes / Q000378:metabolism / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012984:Software; D013329:Structure-Activity Relationship
D016587:Antimutagenic Agents; D018736:DNA Adducts; D009153:Mutagens; D011084:Polycyclic Aromatic Hydrocarbons; D011721:Pyrenes; D009601:Nitroreductases; C032668:1-nitropyrene