Skorpen F, Alm B, Skjelbred C, Aas P A, Krokan H E
UNIGEN Center for Molecular Biology, Norwegian University of Science and Technology, Trondheim.
Chem Biol Interact. 1998 Mar 12;110(1-2):123-36. doi: 10.1016/s0009-2797(98)00002-7.
We have studied the effect of low levels of paracetamol (0.3 and 1.0 mM) on gene-specific DNA repair, recovery of total RNA synthesis and cytotoxicity after exposure of human keratinocyte cells (HaCaT) to ultraviolet (UV) irradiation. Repair of cyclobutane pyrimidine dimers (CPDs) was measured in the transcriptionally active uracil-DNA glycosylase (UNG) and c-MYC loci. Repair of both strands in the UNG gene was consistently lower in the presence of paracetamol, but this reduction reached significance only at 8 h after irradiation and no dose-response was observed. For the c-MYC gene, we found no significant effect of paracetamol on the repair of CPDs, possibly because UV-irradiation is known to induce transcription of the c-MYC gene and enhanced transcription coupled repair might counteract a negative effect of paracetamol on global genome repair. A dose-dependent delay in the recovery of total RNA synthesis after UV exposure was observed in the presence of paracetamol, which also caused a 20% increase in UV-induced cytotoxicity after 24 h. Paracetamol had no significant effect on either RNA synthesis or cell survival in the absence of UV after 24 h, but reduced cell survival by approximately 10% (at 0.3 mM) and 50%, (at 1.0 mM) after 96 h exposure. Our results demonstrate that paracetamol may inhibit gene-specific repair of CPDs by affecting global genome repair and that different genes may be differentially affected.
我们研究了低水平对乙酰氨基酚（0.3和1.0 mM）对人角质形成细胞（HaCaT）暴露于紫外线（UV）照射后基因特异性DNA修复、总RNA合成恢复和细胞毒性的影响。在转录活性尿嘧啶-DNA糖基化酶（UNG）和c-MYC基因座中测量环丁烷嘧啶二聚体（CPD）的修复情况。在对乙酰氨基酚存在的情况下，UNG基因两条链的修复始终较低，但这种降低仅在照射后8小时达到显著水平，且未观察到剂量反应。对于c-MYC基因，我们发现对乙酰氨基酚对CPD修复没有显著影响，这可能是因为已知紫外线照射会诱导c-MYC基因转录，增强的转录偶联修复可能抵消了对乙酰氨基酚对全基因组修复的负面影响。在对乙酰氨基酚存在的情况下，观察到紫外线暴露后总RNA合成恢复存在剂量依赖性延迟，这也导致24小时后紫外线诱导的细胞毒性增加20%。在24小时无紫外线照射的情况下，对乙酰氨基酚对RNA合成或细胞存活均无显著影响，但在暴露96小时后，细胞存活率分别降低约10%（0.3 mM时）和50%（1.0 mM时）。我们的结果表明，对乙酰氨基酚可能通过影响全基因组修复来抑制CPD的基因特异性修复，并且不同基因可能受到不同程度的影响。
