a Avazyme Inc , Durham , North Carolina , USA.
b College of Veterinary Medicine , North Carolina State University , Raleigh , North Carolina , USA.
J Toxicol Environ Health A. 2018;81(18):913-923. doi: 10.1080/15287394.2018.1502560. Epub 2018 Aug 21.
The aim of this study was to (1) determine if the organochlorine artificial sweetener sucralose is metabolized in rat intestine with repeated dosing and (2) examine whether sucralose might bioaccumulate in rat adipose tissue. Sucralose was administered to 10 rats by gavage daily for 40 days at an average dosage of 80.4 mg/kg/day. The dosages were within the range utilized in historical toxicology studies submitted for regulatory approval in North America, Europe, and Asia. Feces and urine were collected individually from each animal for every 24-hr period during the 40-day dosing period. Analysis of the urine and fecal extracts by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) revealed two new biotransformation products that have not previously been reported. These two metabolites are both acetylated forms of sucralose that are less polar and hence more lipophilic than sucralose itself. These metabolites were present in urine and feces throughout the sucralose dosing period and still detected at low levels in the urine 11 days after discontinuation of sucralose administration and 6 days after sucralose was no longer detected in the urine or feces. The finding of acetylated sucralose metabolites in urine and feces do not support early metabolism studies, on which regulatory approval was based, that claimed ingested sucralose is excreted unchanged (i.e. not metabolized). The historical metabolic studies apparently failed to detect these metabolites in part because investigators used a methanol fraction from feces for analysis along with thin layer chromatography and a low-resolution linear radioactivity analyzer. Further, sucralose was found in adipose tissue in rats two weeks after cessation of the 40-day feeding period even though this compound had disappeared from the urine and feces. Thus, depuration of sucralose which accumulated in fatty tissue requires an extended period of time after discontinuation of chemical ingestion. These new findings of metabolism of sucralose in the gastrointestinal tract (GIT) and its accumulation in adipose tissue were not part of the original regulatory decision process for this agent and indicate that it now may be time to revisit the safety and regulatory status of this organochlorine artificial sweetener.
（1）确定经口重复给予后，人工合成甜味剂三氯蔗糖是否在大鼠肠道中代谢；（2）检测三氯蔗糖是否可能在大鼠脂肪组织中生物蓄积。将三氯蔗糖以 80.4mg/kg/天的平均剂量通过灌胃每天给予 10 只大鼠，连续给药 40 天。这些剂量处于在北美、欧洲和亚洲提交的用于监管批准的历史毒理学研究中使用的范围内。在 40 天的给药期间，每只动物单独收集每 24 小时的粪便和尿液。通过超高效液相色谱串联质谱（UHPLC-MS/MS）分析尿液和粪便提取物，发现了两种以前未报道的新的生物转化产物。这两种代谢物均为三氯蔗糖的乙酰化形式，其极性低于三氯蔗糖本身，脂溶性更高。这些代谢物在整个三氯蔗糖给药期间存在于尿液和粪便中，并且在停止三氯蔗糖给药后 11 天和尿液或粪便中不再检测到三氯蔗糖后 6 天，在尿液中仍以低水平检测到。尿液和粪便中乙酰化三氯蔗糖代谢物的发现不支持基于监管批准的早期代谢研究，该研究声称摄入的三氯蔗糖未发生变化（即未代谢）而被排泄。历史代谢研究显然未能检测到这些代谢物，部分原因是研究人员使用粪便的甲醇级分进行分析，同时使用薄层色谱和低分辨率线性放射性分析器。此外，即使这种化合物已经从尿液和粪便中消失，在停止 40 天喂养期两周后，仍在大鼠的脂肪组织中发现了三氯蔗糖。因此，在停止化学物质摄入后，需要经过很长一段时间才能使蓄积在脂肪组织中的三氯蔗糖被清除。这些关于三氯蔗糖在胃肠道（GIT）中的代谢及其在脂肪组织中积累的新发现，不属于该物质原始监管决策过程的一部分，表明现在可能需要重新审视这种有机氯人工甜味剂的安全性和监管状况。
