Guo Z, Smith T J, Wang E, Sadrieh N, Ma Q, Thomas P E, Yang C S
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855.
Carcinogenesis. 1992 Dec;13(12):2205-10. doi: 10.1093/carcin/13.12.2205.
Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, has been shown to inhibit chemical carcinogenesis, possibly due to its ability to block the activation or to enhance the detoxification of chemical carcinogens. The present study was conducted to elucidate the biochemical mechanisms involved by characterizing the effects of PEITC on phase I and phase II xenobiotic-metabolizing enzymes. A single dose of PEITC to F344 rats (1 mmol/kg) decreased the liver N-nitrosodimethylamine demethylase (NDMAd) activity (mainly due to P450 2E1) by 80% at 2 h and the activity of NDMAd remained decreased by 40% at 48 h after treatment. The liver pentoxyresorufin O-dealkylase (PROD) activity and P450 2B1 protein level were elevated 10- and 7-fold at 24 h after treatment respectively. The liver microsomal ethoxyresorufin O-dealkylase (EROD) (mainly due to P450 1A) and erythromycin N-demethylase (mainly due to P450 3A) activities were decreased at 2-12 h after treatment and recovered afterwards. The lung microsomal PROD and EROD activities were not significantly affected; whereas, the nasal microsomal PROD and EROD activities were decreased by 40-50%. After a treatment with PEITC, the rates of oxidative metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were decreased in liver microsomes by 40-60% at 2 h and recovered gradually; the rates in lung microsomes were markedly decreased by 60-70% at 2 h and remained at the decreased level at 24 h; and the rates in nasal mucosa microsomes were decreased gradually with the lowest activities observed at 18 h (50%) followed by a gradual recovery. Furthermore, the treatment with PEITC resulted in a maximal 5-fold increase of NAD(P)H:quinone oxidoreductase and 1.5-fold increase of glutathione S-transferase activities in the liver, but the activities of these two enzymes were not significantly affected in the lung and nasal mucosa. The sulfotransferase activity in the liver was decreased by 32-48% at 24-48 h after treatment; the nasal activity was increased by 1.8- to 2.5-fold, but the lung activity was not significantly changed. The hepatic UDP glucuronosyltransferase activity was slightly decreased at 2 h but slightly increased at 48 h after treatment, but no changes were observed for the lung and nasal activities. The study demonstrates that PEITC selectively affects xenobiotic-metabolizing enzymes in the liver, lung and nasal mucosa and it is especially effective in inhibiting the P450-dependent oxidation of NNK in the lung and of NDMA in the liver.
异硫氰酸苯乙酯（PEITC）是十字花科蔬菜的一种成分，已被证明能够抑制化学致癌作用，这可能归因于其阻断化学致癌物活化或增强其解毒的能力。本研究旨在通过表征PEITC对I相和II相异生物质代谢酶的影响来阐明其中涉及的生化机制。给F344大鼠单次注射PEITC（1 mmol/kg）后，2小时时肝脏N-亚硝基二甲胺脱甲基酶（NDMAd）活性（主要归因于P450 2E1）降低了80%，处理后48小时NDMAd活性仍降低40%。处理后24小时，肝脏戊氧基试卤灵O-脱烷基酶（PROD）活性和P450 2B1蛋白水平分别升高了10倍和7倍。处理后2 - 12小时，肝脏微粒体乙氧基试卤灵O-脱烷基酶（EROD）（主要归因于P450 1A）和红霉素N-脱甲基酶（主要归因于P450 3A）活性降低，之后恢复。肺微粒体PROD和EROD活性未受到显著影响；而鼻微粒体PROD和EROD活性降低了40 - 50%。用PEITC处理后，肝脏微粒体中4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）的氧化代谢速率在2小时时降低了40 - 60%，并逐渐恢复；肺微粒体中的速率在2小时时显著降低了60 - 70%，并在24小时时保持在降低水平；鼻黏膜微粒体中的速率逐渐降低，在18小时时观察到最低活性（50%），随后逐渐恢复。此外，用PEITC处理导致肝脏中NAD(P)H：醌氧化还原酶活性最大增加5倍，谷胱甘肽S-转移酶活性增加1.5倍，但这两种酶的活性在肺和鼻黏膜中未受到显著影响。处理后24 - 48小时，肝脏中的磺基转移酶活性降低了32 - 48%；鼻中的活性增加了1.8至2.5倍，但肺中的活性未发生显著变化。肝脏中的UDP葡萄糖醛酸基转移酶活性在处理后2小时略有降低，但在48小时略有增加，而肺和鼻中的活性未观察到变化。该研究表明，PEITC选择性地影响肝脏、肺和鼻黏膜中的异生物质代谢酶，并且在抑制肺中NNK和肝脏中NDMA的P450依赖性氧化方面特别有效。
