Three points need to be explained: First, the mice model for APAP-induced hepatotoxicity is acceptable, but a group of authors have used the rat model to investigate hepatotoxicity induced by acetaminophen. For example, Rajasekaran and Periyasamy (2012) and Pingili et al. (2019)(1,2) used rats for their studies. The Pingili et al. study has been mentioned in the Letter to the Editor written by Jaeschke and Ramachandran. On the other hand, we were not looking for any reflection between rat or mice and human, but our study was done to investigate the interaction between chrysin and APAP-induced hepatotoxicity. Rat models are used to show histopathologic indices of APAP-induced hepatotoxicity and inflammatory complications.(3−7) Second, based on the study by Pingili et al. (2019), chrysin may inhibit CYP2E1, CYP1A2, and CYP3A4 activity in long-term treatment in rats. Though this is a worthy finding, it does not completely support the hypothesis of the protective effect of chrysin, since, despite treatment with chrysin, we observe histopathologic findings consistent with APAP-induced hepatotoxicity. This means that, despite this inhibition, some APAP may escape this possible mechanism and may be affected by enzymes and produce NAPQUI. Therefore, other effects of chrysin such as antioxidant or anti-inflammatory effects may involve its protective effect. Although inhibition of the enzymes is a very important and effective mechanism, it is complicated case and cannot be completely supported by only a few studies and other mechanisms of action as protective agent of chrysin should be considered.(8−10) Third, it seems that something went wrong in the Letter to the Editor. Based on the setting of our investigation, first we challenged the rats with APAP doses and then the animals received daily doses of chrysin for 14 consecutive days. According to our study, the rats were divided into nine groups of six, and APAP (1500 mg/kg) was administered in three divided doses of 500 mg/kg in all groups, except for the control, the second, and the seventh groups (receiving 40 mg/kg chrysin). However, the respected authors wrote in their Letter: “The authors treated rats for 14 days with various doses of chrysin and then challenged the animals with 3 doses of 1 500 mg/kg APAP every 2 h.” On the other hand, we did not look for antidote action of chrysin because we assumed that chrysin might play a protective role as a treatment agent against APAP-induced hepatotoxicity. Our investigation was conducted to find out the possible protective effect of chrysin in long-term administration after receiving toxic doses of APAP. Beyond the effects of chrysin as P450 inhibitor, it may be expected that one part of the protective effect comes from chrysin’s antioxidant(1,8) and anti-inflammatory actions.(11) There are a few reports about chrysin’s protective effects. However, one needs to extend the research around this topic and more investigations are required.(12−14) This article references 14 other publications.

中文翻译：

---

对Hartmut Jaeschke和Anup Ramachandran写给我们的信的信，关于我们的文章“胰蛋白酶在预防对乙酰氨基酚引起的大鼠肝毒性中的作用”

需要解释三点：首先，APAP诱导的肝毒性的小鼠模型是可以接受的，但是一组作者已经使用大鼠模型研究了对乙酰氨基酚引起的肝毒性。例如，Rajasekaran和Periyasamy（2012）和Pingili等。（2019）（1,2）使用大鼠进行研究。Pingili等。Jaeschke和Ramachandran写给编辑的信中提到了这项研究。另一方面，我们并不想在大鼠或小鼠与人之间产生任何反射，但是我们进行了研究以研究质与APAP诱导的肝毒性之间的相互作用。大鼠模型用于显示APAP诱导的肝毒性和炎症并发症的组织病理学指标。（3-7）其次，基于Pingili等人的研究。（2019），chrysin可能抑制CYP2E1，CYP1A2，和CYP3A4在大鼠长期治疗中的活性。尽管这是一个值得发现的发现，但它并不完全支持关于菊花蛋白的保护作用的假设，因为尽管用菊花蛋白进行了治疗，但我们仍观察到了与APAP诱导的肝毒性一致的组织病理学发现。这意味着，尽管有这种抑制作用，但某些APAP可能会逃避这种可能的机制，并可能受到酶的影响并产生NAPQUI。因此，菊花蛋白的其他作用，例如抗氧化剂或抗炎作用，可能涉及其保护作用。尽管酶的抑制是非常重要和有效的机制，但它的情况很复杂，只有很少的研究不能完全支持，还应考虑其他作为菊花蛋白保护剂的作用机制。（8-10）第三，似乎在给编辑的信中有问题。根据我们的研究背景，我们首先以APAP剂量对大鼠进行攻击，然后每天连续14天给动物每天服用chrysin。根据我们的研究，将大鼠分为9组，每组6只，除对照组，第二组和第七组外，所有组均以500 mg / kg的三个分次剂量给予APAP（1500 mg / kg） （接受40毫克/公斤的白杨素）。但是，受人尊敬的作者在信中写道：除对照组，第二组和第七组（接受40 mg / kg chrysin）外，所有组均以500 mg / kg的三个分次剂量分别给予APAP（1500 mg / kg）。但是，受人尊敬的作者在信中写道：除对照组，第二组和第七组（接受40 mg / kg chrysin）外，所有组均以500 mg / kg的三个分次剂量分别给予APAP（1500 mg / kg）。但是，受人尊敬的作者在信中写道：作者用不同剂量的胰蛋白酶处理大鼠14天，然后每2小时用3剂量的1500 mg / kg APAP攻击动物。另一方面，我们并没有寻求菊花素的解毒作用，因为我们认为菊花素可能作为针对APAP诱导的肝毒性的治疗剂起保护作用。我们进行了调查，以了解在接受有毒剂量的APAP后，长期服用菊花素可能具有的保护作用。除了of链霉菌素作为P450抑制剂的作用外，可以预期的一部分保护作用还来自于ry链菌素的抗氧化剂（1,8）和抗炎作用。（11）关于链菌素的保护作用的报道很少。但是，需要围绕此主题进行更多的研究，并且需要进行更多的研究。（12-14）本文引用了其他14个出版物。