Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice.,Chemical Research in Toxicology

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Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-06-01 , DOI: 10.1021/acs.chemrestox.0c00161
Qi Hu ₁ , Pedro Corral ₁ , Sreekanth C Narayanapillai _{1,

2} , Pablo Leitzman ₂ , Pramod Upadhyaya ₃ , M Gerard O'Sullivan _{3,

4} , Stephen S Hecht ₃ , Junxuan Lu ₅ , Chengguo Xing _{1,

2}

Affiliation

Our early studies demonstrated an impressive chemopreventive efficacy of dihydromethysticin (DHM), unique in kava, against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice in which DHM was supplemented in the diet. The current work was carried out to validate the efficacy, optimize the dosing schedule, and further elucidate the mechanisms using oral bolus dosing of DHM. The results demonstrated a dose-dependent chemopreventive efficacy of DHM (orally administered 1 h before each of the two NNK intraperitoneal injections, 1 week apart) against NNK-induced lung adenoma formation. Temporally, DHM at 0.8 mg per dose (∼32 mg per kg body weight) exhibited 100% lung adenoma inhibition when given 3 and 8 h before each NNK injection and attained >93% inhibition when dosed at either 1 or 16 h before each NNK injection. The simultaneous treatment (0 h) or 40 h pretreatment (−40 h) decreased lung adenoma burden by 49.8% and 52.1%, respectively. However, post-NNK administration of DHM (1–8 h after each NNK injection) was ineffective against lung tumor formation. In short-term experiments for mechanistic exploration, DHM treatment reduced the formation of NNK-induced O⁶-methylguanine (O⁶-mG, a carcinogenic DNA adduct in A/J mice) in the target lung tissue and increased the urinary excretion of NNK detoxification metabolites as judged by the ratio of urinary NNAL-O-gluc to free NNAL, generally in synchrony with the tumor prevention efficacy outcomes in the dose scheduling time-course experiment. Overall, these results suggest DHM as a potential chemopreventive agent against lung tumorigenesis in smokers, with O⁶-mG and NNAL detoxification as possible surrogate biomarkers.

中文翻译：

在烟草致癌物 NNK 之前口服二氢迷幻素可有效预防 A/J 小鼠肺部肿瘤的发生。

我们的早期研究表明，卡瓦中独特的二氢迷幻素 (DHM) 对烟草致癌物 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 诱导的 A/J 小鼠肺部肿瘤发生具有令人印象深刻的化学预防功效其中DHM是在饮食中补充的。目前的工作是验证 DHM 的疗效、优化给药方案并进一步阐明口服推注给药的机制。结果表明，DHM（两次 NNK 腹腔注射前 1 小时口服，间隔 1 周）对 NNK 诱导的肺腺瘤形成具有剂量依赖性化学预防功效。暂时而言，每次 NNK 注射前 3 小时和 8 小时给药时，每次剂量 0.8 mg（约 32 mg/kg 体重）的 DHM 表现出 100% 肺腺瘤抑制作用，而在每次 NNK 注射前 1 或 16 小时给药时，则达到 >93% 的抑制作用注射。同时治疗（0小时）或40小时预处理（-40小时）分别使肺腺瘤负担减少49.8%和52.1%。然而，NNK 后给予 DHM（每次 NNK 注射后 1-8 小时）对肺部肿瘤形成无效。在机制探索的短期实验中，DHM 治疗减少了 NNK 诱导的O ⁶ -甲基鸟嘌呤（ O ⁶ -mG，A/J 小鼠中的致癌 DNA 加合物）在靶肺组织中的形成，并增加了 NNK 的尿排泄通过尿 NNAL- O -gluc 与游离 NNAL 的比率来判断解毒代谢物，通常与剂量安排时程实验中的肿瘤预防功效结果同步。总体而言，这些结果表明 DHM 作为针对吸烟者肺部肿瘤发生的潜在化学预防剂， O ⁶ -mG 和 NNAL 解毒作为可能的替代生物标志物。

更新日期：2020-07-20

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