Culvenor C C, Edgar J A, Jago M V, Qutteridge A, Peterson J E, Smith L W
Chem Biol Interact. 1976 Mar;12(3-4):299-324. doi: 10.1016/0009-2797(76)90046-6.
62 pyrrolizidine alkaloids and derivatives have been screened for acute and chronic hepato- and pneumotoxicity by the single dose method previously described. This procedure is satisfactory for the compounds of medium to high hepatotoxicity but failed to detect toxicity in certain other compounds of known, low hepatotoxicity. New findings significant in relation to hepatotoxicity are as follows: (i) On a molar basis, diesters of heliotridine and retronecine are about 4 times as toxic as the respective mono-esters and heliotridine esters are 2-4 times as toxic as retronecine esters. (ii) Crotanecine esters are less toxic than retronecine esters, and the 6,9-diester madurensine, 2-4 times less toxic than the 7,9-diester anacrotine (the difference being ascribed to there being only one reactive alkylating centre in the toxic metabolite from madurensine). (iii) Hepatotoxicity was confirmed for 7-angelylheliotridine but not observed for 9-angelyheliotridine and 7- and 9-angelylretronecine. (iv) Other significant compounds failing to induce hepatotoxicity were 9-pivalyl- and 7,9-dipivalyheliotridine, the alpha- and beta-epoxides of monocrotaline, 7-angelyl-1-methylenepyrrolizidine and the methiodides of monocrotaline and senecionine. The following compounds are readily converted by rat liver microsomes in vitro into dehydroheliotridine (or dehydroretronecine): 7- and 9-angelyheliotridine, 7- and 9-angelylretronecine, 7,9-dipivalylheliotridine and otosenine. 7,9-Divalerylheliotridine, the alpha- and beta-epoxides of monocrotaline, and retusamine yield pyrrolic metabolites more slowly. The preparation and characterisation of several alkaloid derivatives are described. Chronic lung lesions were produced by most compounds which gave chronic liver lesions, although a higher dose was required in some instances. This requirement may sometimes mean that chronic lung lesions cannot be induced because of the intervention of acute or peracute deaths. Apart from this factor, structure activity requirements for pneumotoxicity are the same as for hepatotoxicity, consistent with their being both caused by the same toxic metabolites.
通过先前描述的单剂量方法，对62种吡咯里西啶生物碱及其衍生物进行了急性和慢性肝毒性及肺毒性筛查。该方法对于中高肝毒性化合物来说是令人满意的，但未能检测出某些已知低肝毒性化合物的毒性。与肝毒性相关的新发现如下：(i) 从摩尔基础来看，天芥菜定和倒千里光裂碱的二酯毒性约为各自单酯的4倍，且天芥菜定酯的毒性是倒千里光裂碱酯的2 - 4倍。(ii) 巴豆千里光裂碱酯的毒性低于倒千里光裂碱酯，6,9 - 二酯马杜来新的毒性比7,9 - 二酯乌头千里光裂碱低2 - 4倍（差异归因于马杜来新的毒性代谢产物中只有一个反应性烷基化中心）。(iii) 7 - 当归酰天芥菜定的肝毒性得到证实，但9 - 当归酰天芥菜定以及7 - 和9 - 当归酰倒千里光裂碱未观察到肝毒性。(iv) 其他未诱导肝毒性的重要化合物有9 - 新戊酰基 - 和7,9 - 二新戊酰基天芥菜定、野百合碱的α - 和β - 环氧化物、7 - 当归酰 - 1 - 亚甲基吡咯里西啶以及野百合碱和千里光碱的甲碘化物。以下化合物在体外容易被大鼠肝微粒体转化为脱氢天芥菜定（或脱氢倒千里光裂碱）：7 - 和9 - 当归酰天芥菜定、7 - 和9 - 当归酰倒千里光裂碱、7,9 - 二新戊酰基天芥菜定和欧托千里光碱。7,9 - 二戊酰基天芥菜定、野百合碱的α - 和β - 环氧化物以及瑞图胺生成吡咯代谢产物的速度较慢。描述了几种生物碱衍生物的制备和特性。大多数导致慢性肝损伤的化合物也会产生慢性肺部损伤，尽管在某些情况下需要更高剂量。这个要求有时可能意味着由于急性或超急性死亡的干预而无法诱导出慢性肺部损伤。除了这个因素外，肺毒性的构效要求与肝毒性相同，这与它们都是由相同的毒性代谢产物引起的一致。
