Sangster S A, Caldwell J, Smith R L
Food Chem Toxicol. 1984 Sep;22(9):707-13. doi: 10.1016/0278-6915(84)90197-2.
The effect of dose size on the metabolism of trans-anethole was investigated in rodents over the dose range 0.05-1500 mg/kg. trans-[methoxy-14C]Anethole was administered to female Wistar rats by gavage and to male CD-1 mice by ip injection. Urine, faeces and 14CO2 in expired air were collected and their 14C content was measured. Urinary metabolites were separated as described by Sangster et al. (Fd Chem. Toxic. 1984, 22, 695) and quantitated by radioHPLC and TLC. The major route of metabolism of trans-anethole in rodents is via oxidative O-demethylation and the importance of this route was found to decrease with increasing dose from 56 and 72% of the dose at 0.05 mg/kg to 32 and 35% of the dose at 1500 mg/kg in rats and mice, respectively. Over this dose range the elimination of 14C-labelled urinary metabolites increased significantly in both species. There was a species-specific regioselectivity in the side-chain oxidation of anethole. The rat favoured the epoxidation route, resulting in the elimination in the urine of two 1-(4'-methoxyphenyl)propane-1,2-diol isomers, elimination of which together rose from 2 to 15% of the dose over the dose range studied. In contrast the mouse favoured omega-oxidation, yielding cinnamyl compounds and 4-methoxybenzoic and 4-methoxyhippuric acids, the elimination of the latter two rising from 10 to 42% of the dose over the dose range studied. The species differences in metabolism, and the significance of the effect of increasing dose on the metabolic route are discussed with reference to the guidance these results could give in the assessment of the risk to man from dietary exposure to trans-anethole and related compounds.
在0.05 - 1500 mg/kg的剂量范围内，研究了剂量大小对啮齿动物中反式茴香脑代谢的影响。通过灌胃给雌性Wistar大鼠施用反式-[甲氧基-¹⁴C]茴香脑，通过腹腔注射给雄性CD-1小鼠施用。收集尿液、粪便和呼出空气中的¹⁴CO₂，并测量它们的¹⁴C含量。尿代谢物按照Sangster等人（《食品化学与毒理学》，1984年，22卷，695页）所述进行分离，并通过放射性高效液相色谱法和薄层色谱法进行定量。反式茴香脑在啮齿动物中的主要代谢途径是通过氧化O-去甲基化，并且发现该途径的重要性随着剂量增加而降低，在大鼠和小鼠中，该途径在0.05 mg/kg剂量时分别占剂量的56%和72%，在1500 mg/kg剂量时分别降至32%和35%。在这个剂量范围内，两种物种中¹⁴C标记的尿代谢物的消除都显著增加。茴香脑侧链氧化存在物种特异性区域选择性。大鼠倾向于环氧化途径，导致尿液中消除两种1-(4'-甲氧基苯基)丙烷-1,2-二醇异构体，在所研究的剂量范围内，这两种异构体的消除总量从剂量的2%增加到15%。相比之下，小鼠倾向于ω-氧化，产生肉桂基化合物以及4-甲氧基苯甲酸和4-甲氧基马尿酸，在所研究的剂量范围内，后两者的消除量从剂量的10%增加到42%。结合这些结果在评估人类通过饮食接触反式茴香脑及相关化合物的风险时可能提供的指导，讨论了代谢的物种差异以及剂量增加对代谢途径影响的意义。
