Yoxall Victoria, Kentish Peter, Coldham Nick, Kuhnert Nikolai, Sauer Maurice J, Ioannides Costas
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, United Kingdom.
Int J Cancer. 2005 Nov 10;117(3):356-62. doi: 10.1002/ijc.21191.
The principal objectives of our study were to ascertain whether sulforaphane, at dietary levels of intake, modulates rat hepatic cytochrome P450 and phase II enzyme systems and to evaluate the impact of such changes in the chemopreventive activity of this isothiocyanate. Animals were exposed to sulforaphane in their drinking water for 10 days, equivalent to daily doses of 3 and 12 mg/kg. Depentylation of pentoxyresorufin decreased and was paralleled by a decline in CYP2B apoprotein levels. At the higher dose, erythromycin N-demethylase activity declined and was accompanied by a similar decrease in CYP3A2 apoprotein levels. However, sulforaphane treatment upregulated CYP1A2 levels, determined immunologically, but the dealkylations of methoxy- and ethoxyresorufin were not similarly increased. Hepatic S9 preparations from sulforaphane-treated rats were less effective than control preparations in converting IQ (2-amino-3-methylimidazo-[4,5-f]quinoline) to mutagenic intermediates in the Ames test. To clarify the underlying mechanism, in vitro studies were undertaken. In beta-naphthoflavone-treated rats, the inhibition by sulforaphane of the O-dealkylations of methoxy- and ethoxyresorufin was enhanced if the isothiocyanate was preincubated in the presence of NADPH. It may be inferred that sulforaphane induces hepatic CYP1A2 but the enzyme is not catalytically competent because of bound sulforaphane metabolite(s). Finally, sulforaphane stimulated, in a dose-dependent fashion, quinone reductase but failed to influence glutathione S-transferase, epoxide hydrolase and glucuronosyl transferase activities. It is concluded that, even at dietary doses, sulforaphane can modulate the xenobiotic-metabolising enzyme systems, shifting the balance of carcinogen metabolism toward deactivation, and this may be an important mechanism of its chemopreventive activity.
我们研究的主要目的是确定膳食摄入水平的萝卜硫素是否会调节大鼠肝脏细胞色素P450和II相酶系统，并评估这种变化对该异硫氰酸盐化学预防活性的影响。将动物在饮用水中接触萝卜硫素10天，相当于每日剂量3和12 mg/kg。戊氧基试卤灵的脱戊基化减少，同时CYP2B载脂蛋白水平下降。在较高剂量下，红霉素N-脱甲基酶活性下降，同时CYP3A2载脂蛋白水平也有类似下降。然而，经免疫测定，萝卜硫素处理上调了CYP1A2水平，但甲氧基和乙氧基试卤灵的脱烷基化并未同样增加。在Ames试验中，来自经萝卜硫素处理大鼠的肝脏S9制剂在将IQ（2-氨基-3-甲基咪唑-[4,5-f]喹啉）转化为诱变中间体方面比对照制剂效果更差。为了阐明潜在机制，进行了体外研究。在β-萘黄酮处理的大鼠中，如果异硫氰酸盐在NADPH存在下预孵育，则萝卜硫素对甲氧基和乙氧基试卤灵O-脱烷基化的抑制作用会增强。可以推断，萝卜硫素诱导肝脏CYP1A2，但由于结合的萝卜硫素代谢物，该酶没有催化活性。最后，萝卜硫素以剂量依赖的方式刺激醌还原酶，但未能影响谷胱甘肽S-转移酶、环氧化物水解酶和葡萄糖醛酸转移酶活性。得出的结论是，即使在膳食剂量下，萝卜硫素也可以调节外源性物质代谢酶系统，使致癌物代谢平衡朝着失活方向转变，这可能是其化学预防活性的重要机制。
