Metabolism of N-Containing Polycyclic Aromatic Hydrocarbons

本研究旨在建立基因毒性含n多环芳烃激活的代谢过程。本次联合研究的同行之一Jerina提出了多环芳烃活化的bay-region理论，但对芳烃体系中含氮、氧等杂原子的活化尚未有系统的研究。我们发现喹啉的活化形式可能是1,4 -水合喹啉的2,3 -氧化物，这是一种不同于多环芳烃的海湾区环氧化合物的新型活化环氧化合物。卤代喹啉和甲基取代喹啉衍生物的代谢进一步证明了这一假说。基于这种活化甲烷反应，我们提出，当氟取代喹啉环的-3位时，这些衍生物将完全丧失遗传毒性。该建议已通过几个实例得到了实验证明。在这项为期3年的联合研究的后半部分，我们将研究范围扩展到木质素相关的生物活性化合物，即含氧高分子芳香族化合物。我们发现几种天然和合成木质素具有多种生物活性，包括抗病毒和抗菌活性，以及免疫增强活性。木质素骨架结构是其抗病毒活性所必需的，而一些附着在木质素骨架上的半纤维素附属物也是其免疫增强活性所必需的。这一研究结果表明，无论是天然的还是合成的木质化材料，都是一种潜在的药用资源。

This research aimed at establishment of the metabolic process involved in the activation of genotoxic N-containing polycylic aromatic hydrocarbons. The bay-region theory was proposed by Jerina, one of the counterparts of this joint research, on the activation of polycyclic aromatic hydrocarbons, but no systematic study hasnot yet been achieved on the activation of those containing hetero atom(s) such nitrogen and oxygen in the aromatic system. We have revealed that the activated form of quinoline may be the 2, 3-oxide of quinoline 1, 4-hydrate, which is a new type of activated epoxide different from the bay-region epoxides proposed to polycyclic aromatic hydrocarbons. This working hypothesis has been further evidenced by the matabolism of halogno- and methyl-substituted quinoline derivatives. Based on this activation methanism, we proposed that, when fluorine is substituted on the position-3 of the quinoline ring, those derivatives would be completely deprived of genotoxicity. This proposal has been experimentally proven with several examples.In the latter part of this 3-year joint research, we have extended the study to the bioactive lignin-related compounds, which are the oxygen-containing polymeric aromatic compounds. We found that several natural and synthetic lignins had diverse biological activities including antiviral and antimicrobial activity, and in addition, immunopotenting activity. Lignin skeletal structure is essentially required for the antiviral activity, whereas some hemicellulose appendages attached to the lignin skeleton are also required for immunopotentiating activity leading to antimicrobial activity. This research strongly suggests that more attention should be paid to the lignified materials, both natural and synthetic, as a potential medicinal resource.