Fisher Craig D, Augustine Lisa M, Maher Jonathan M, Nelson David M, Slitt Angela L, Klaassen Curtis D, Lehman-McKeeman Lois D, Cherrington Nathan J
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
Drug Metab Dispos. 2007 Jun;35(6):995-1000. doi: 10.1124/dmd.106.014340. Epub 2007 Mar 12.
Garlic oil (GO) contains several linear sulfur compounds, including diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), that induce drug-metabolizing enzymes such as CYP2B and NAD(P)H quinone oxidoreductase 1 (NQO1). CYP2B and NQO1 are primarily regulated by constitutive androstane receptor (CAR) and nuclear factor E2-related factor 2 (Nrf2) transcription factors, respectively. The purpose of this study was to determine whether GO and its specific constituents induce these two enzymes via CAR and Nrf2 activation. Female Wistar-Kyoto (WKY) rats express little CAR protein and exhibit less induction of CYP2B1/2 than males. GO, DAS, and DADS, but not DATS, induced CYP2B1/2 mRNA levels to a greater extent in WKY males than in females, suggesting CAR activation. Conversely, DAS induced NQO1 levels equally in WKY males and females, indicating CAR-independent induction in rats. DAS, but not GO, DADS, or DATS, induced CYP2B10 mRNA levels 530-fold in wild-type (WT) mice, whereas this induction was attenuated in CAR(-/-) mice. DAS induced NQO1 in WT and CAR(-/-) mice equally, suggesting CAR-independent induction in mice. DAS induced NQO1 5-fold in WT mice, whereas induction was completely absent in Nrf2(-/-) mice, indicating DAS also activates Nrf2. DAS induction of CYP2B10 mRNA was independent of Nrf2 presence or absence. In in vivo transcription assays, DAS activated the human CYP2B6 promoter, and the antioxidant response element of the human NQO1 promoter, respectively. These studies indicate that GO constituents, particularly DAS, activate CAR and Nrf2 to induce drug-metabolizing enzymes.
大蒜油（GO）含有多种线性硫化合物，包括二烯丙基硫醚（DAS）、二烯丙基二硫醚（DADS）和二烯丙基三硫醚（DATS），这些化合物可诱导药物代谢酶，如CYP2B和NAD（P）H醌氧化还原酶1（NQO1）。CYP2B和NQO1分别主要受组成型雄烷受体（CAR）和核因子E2相关因子2（Nrf2）转录因子调控。本研究的目的是确定GO及其特定成分是否通过激活CAR和Nrf2来诱导这两种酶。雌性Wistar-Kyoto（WKY）大鼠表达的CAR蛋白很少，且与雄性相比，CYP2B1/2的诱导程度较低。GO、DAS和DADS，但不包括DATS，在WKY雄性大鼠中比在雌性大鼠中更能诱导CYP2B1/2 mRNA水平升高，提示CAR被激活。相反，DAS在WKY雄性和雌性大鼠中同等程度地诱导NQO1水平，表明在大鼠中存在不依赖CAR的诱导作用。DAS而非GO、DADS或DATS可使野生型（WT）小鼠的CYP2B10 mRNA水平升高530倍，而在CAR（-/-）小鼠中这种诱导作用减弱。DAS在WT和CAR（-/-）小鼠中同等程度地诱导NQO1，提示在小鼠中存在不依赖CAR的诱导作用。DAS可使WT小鼠的NQO1诱导5倍，而在Nrf2（-/-）小鼠中完全没有诱导作用，表明DAS也可激活Nrf2。DAS对CYP2B10 mRNA的诱导与Nrf2的存在与否无关。在体内转录试验中，DAS分别激活了人CYP2B6启动子和人NQO1启动子的抗氧化反应元件。这些研究表明，GO成分，特别是DAS，可激活CAR和Nrf2以诱导药物代谢酶。
