Stresser D M, Williams D E, Griffin D A, Bailey G S
Department of Food Science and Technology, Oregon State University, Corvallis 97331-6602, USA.
Drug Metab Dispos. 1995 Sep;23(9):965-75.
This study describes the disposition and excretion of indole-3-carbinol (I3C), a natural dietary tumor modulator and candidate chemopreventive agent, in male Fisher 344 rats after continuous dietary or a single oral administration. Steady-state urinary and fecal excretion were attained 40 and 112 hr, respectively, after commencing continuous exposure. These two routes accounted for approximately 75% of the administered dose, of which 77% appeared in feces. After 7 days of 2,000 ppm dietary I3C, a mean of 1,154 microM I3C eq was found in liver, of which 17% was present as extractable, unbound I3C derivatives. Total equivalents in liver decreased to 643 and 411 microM 24 and 48 hr later, respectively, for animals returned to control diet. Mean levels of I3C eq in lung decreased from 436 to 219 microM, and blood levels decreased from 320 to 208 microM over the same 48-hr period. After administration of 1 mmol/kg radioinert I3C (a comparable daily dose as in the feeding study) for 6 days, animals were given 1 mmol/kg [3H]I3C. Mean liver levels were 257, 283, and 541 microM I3C eq at 1.5, 3, and 6 hr after dosing, and these levels represented 0.97%, 1.34%, and 2.45% of the total I3C dose administered, respectively. Concentrations of I3C eq changed little in blood, kidney, tongue, or lung over this time period. HPLC analysis of ethyl acetate extracts of liver from rats given an oral dose revealed 24 distinct [3H]I3C-derived peaks. Two of the predominant peaks were identified as 3,3'-diindolylmethane (I33', a linear dimer of I3C) and [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LT, a linear trimer). A novel I3C metabolite was identified as 1-(3-hydroxymethyl)-indolyl-3-indolylmethane (HI-IM). Hepatic levels of these metabolites and three major, but unidentified, products were between 1.0 and 13.1 microM; highest levels were observed at 6 hr or, for HI-IM, at 1.5 hr postdosing. Parent I3C was not detected in liver extracts, whereas the potent Ah receptor agonist 3,2-b-indolocarbazole (ICZ) was estimated at 1.6 nM. These data suggest that neither I33', LT, or ICZ alone reach sufficient hepatic concentration to account for cytochrome P450IA induction by dietary I3C, or provide effective inhibition of microsomal bioactivation of the hepatocarcinogen aflatoxin B1; however, the total hepatic mixture of I3C derivatives may be sufficient to provide both modulatory responses in the rat.
本研究描述了吲哚 - 3 - 甲醇（I3C），一种天然膳食肿瘤调节剂和潜在化学预防剂，在雄性Fisher 344大鼠经持续膳食或单次口服给药后的处置和排泄情况。在开始持续暴露后，分别于40小时和112小时达到稳态尿排泄和粪排泄。这两种途径约占给药剂量的75%，其中77%出现在粪便中。在给予2000 ppm膳食I3C 7天后，肝脏中平均发现1154 μM I3C当量，其中17%以可提取的未结合I3C衍生物形式存在。对于恢复到对照饮食的动物，24小时和48小时后肝脏中的总当量分别降至643 μM和411 μM。在相同的48小时期间，肺中I3C当量的平均水平从436 μM降至219 μM，血液水平从320 μM降至208 μM。在给予1 mmol/kg放射性惰性I3C（与喂养研究中相当的日剂量）6天后，给动物给予1 mmol/kg [3H]I3C。给药后1.5小时、3小时和6小时肝脏中的平均水平分别为257 μM、283 μM和541 μM I3C当量，这些水平分别占总给药I3C剂量的0.97%、1.34%和2.45%。在此时间段内，血液、肾脏、舌头或肺中I3C当量的浓度变化很小。对口服给药大鼠肝脏的乙酸乙酯提取物进行HPLC分析，发现24个不同的[3H]I3C衍生峰。两个主要峰被鉴定为3,3'-二吲哚基甲烷（I33'，I3C的线性二聚体）和[2 - （吲哚 - 3 - 基甲基） - 吲哚 - 3 - 基]吲哚 - 3 - 基甲烷（LT，线性三聚体）。一种新的I3C代谢物被鉴定为1 - （3 - 羟甲基） - 吲哚基 - 3 - 吲哚基甲烷（HI - IM）。这些代谢物和三种主要但未鉴定的产物的肝脏水平在1.0至13.1 μM之间；在给药后6小时或HI - IM在给药后1.5小时观察到最高水平。在肝脏提取物中未检测到母体I3C，而强效Ah受体激动剂3,2 - b - 吲哚咔唑（ICZ）估计为1.6 nM。这些数据表明，单独的I33'、LT或ICZ均未达到足以解释膳食I3C诱导细胞色素P450IA的肝脏浓度，也未提供对肝癌致癌物黄曲霉毒素B1微粒体生物活化的有效抑制；然而，I3C衍生物的肝脏总混合物可能足以在大鼠中提供两种调节反应。
