In vivo metabolites of cannabinol identified as fatty acid conjugates
In vivo metabolites of cannabinol identified as fatty acid conjugates
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大麻酚的体内代谢物被鉴定为脂肪酸缀合物
DOI：
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发表时间：
1978
期刊：
影响因子：
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通讯作者：
M. Widman
中科院分区：
文献类型：
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作者：
W. Yisak;S. Agurell;J. Lindgren;M. Widman
大麻酚(CBN)是大麻的主要成分，最近的体内代谢研究表明，CBN具有复杂的代谢模式。已经报道了C-7位以及戊基侧链上每个碳的单羟基化(Burstein&Varanelli 1975；Wall，Brine&Perez-Reyes，1976；Yisak，Widman等人，1977)、二羟基化(Burstein&Varanelli 1975，Yisak等人1977)、氧化成醛(Yisak等人，1977)、酸和羟基酸(Burstein&Varanelli，1975；Wall和其他人，1976；Yisak等人，1977)以及与8-葡萄糖醛酸的共轭作用(Harvey，Martin&Paton，1977)。此外，作为A‘-四氢大麻酚(A1-THC)的代谢物，CBN和CBN衍生物也被分离出来(Ben-Zvi，Bergen&Burstein，1974；Widman，Nordqvist等，1974；McCallum，Yagen等，1975；Ben-Zvi，Bergen等，1976)。最近，Leight，Fentiman&Foltz(1976)报道了7-羟基A1和7-羟基-A6-THC的新型脂肪酸结合物在大鼠体内长期保留。现在，我们希望报道从大鼠粪便中分离的CBN的体内代谢产物4“-羟基、5”-羟基和7-羟基CBN的脂肪酸结合物的分离和性质。~(14)C-CBN经薄层层析(T.1.C.)放化纯度大于97%。和气相色谱(G.C.)12只SD大鼠(200~250g)尾静脉注射比活度为8.0pCI的L(100 mg·kg~(-1))，剂量为70%乙醇。收集尿液和粪便6天，并如前所述进行放射性检测(Yisak和其他人，1977)。冷冻干燥后的细碎粪便用轻质石油提取(b.p。40-60“)(1000毫升)，使用索氏萃取器。萃取物占粪便中放射性的19%，色谱柱为Florisil柱(160g；1.5×115 cm)，用乙醚-轻质石油(1：9)洗脱。洗脱液在Sephadex LH-20柱(1×70 cm)上有两个放射性组分，用轻质石油-氯仿(1：1)洗脱。T.L.C.洗脱体积(Ve)为30-50ml的组分所含的代谢物比CBN的极性低，而Ve为125-160ml的组分所得的CBN不变。T.1.C.代谢产物组分(VE 30-50毫升)的纯化(Yisak等人，1977)使用乙醚-轻质石油(1：9)作为溶剂体系产生了两个放射性谱带。色谱柱为VARIAN 2100(1.06m x 2 mm I.D.玻璃柱，3%SE-30在100-120目的GC-Chrom Q上，每条带的三甲基硅烷化代谢物显示带1含有两个Metabol-1.
Recent in vivo metabolic studies of cannabinol (CBN), a major component of Cannabis sativa, have shown that CBN has a complex metabolic pattern. Monohydroxylation at the C-7 position as well as at each of the carbons of the pentyl side chain (Burstein & Varanelli 1975; Wall, Brine & Perez-Reyes, 1976; Yisak, Widman & others, 1977), dihydroxylation (Burstein & Varanelli 1975, Yisak & others 1977), oxidation to aldehyde (Yisak & others, 1977), acids and hydroxy acids (Burstein & Varanelli, 1975; Wall & others, 1976; Yisak & others, 1977) and conjugation with 8-glucuronic acid (Harvey, Martin & Paton, 1977) have been reported. Furthermore CBN and CBN derivatives have also been isolated (Ben-Zvi, Bergen & Burstein, 1974; Widman, Nordqvist & others, 1974; McCallum, Yagen & others, 1975; Ben-Zvi, Bergen & others, 1976) as metabolites of A'-tetrahydrocannabinol (A1-THC). Recently, Leighty, Fentiman & Foltz (1976) reported long retained novel fatty acid conjugates of 7-hydroxyA1and 7-hydroxy-A6-THC in the rat. We now wish to report the isolation and characterization of fatty acid conjugates of 4"-hydroxy-, 5"-hydroxyand 7-hydroxyCBN as in vivo metabolites of CBN isolated from rat faeces. 14C-CBN with a radiochemical purity greater than 97 % according to thin-layer chromatography (t.1.c.) and gas chromatography (g.c.) and a specific activity of 8.0 pCi mmol-l was administered (100 mg kg-I) via the tail vein in 70% aqueous ethanol to 12 Sprague-Dawley rats (200-250 g). Urine and faeces were collected for six days and assayed for radioactivity as described earlier (Yisak & others, 1977). The lyophilized and finely ground faeces was extracted with light petroleum (b.p. 40-60") (1000 ml) using a soxhlet extractor. The extract, which accounted for 19 % of the radioactivity in the faeces, was chromatographed on a Florisil column(l60 g; 1.5 x 115 cm) and eluted with ether-light petroleum (1 :9). The eluate afforded two radioactive fractions on the Sephadex LH-20 column (1 x 70 cm) eluted with light petroleum-chloroform (1 : 1). The fraction with the elution volume (Ve) of 30-50 ml contained metabolites less polar than CBN on t.l.c., while the fraction with the Ve of 125-160 ml afforded unchanged CBN. Purification of the metabolite fraction (Ve 30-50 ml) by t.1.c. (Yisak & others, 1977) using ether-light petroleum (1 : 9) as the solvent system yielded two radioactive bands. Gas chromatography at 300" on a Varian 2100 (1.06 m x 2 mm i.d. glass column, 3 % SE-30 on 100-120 mesh Gas-Chrom Q of the trimethyl silylated metabolites from each band showed band 1 to contain two metabol-