Zhang D, Freeman J P, Sutherland J B, Walker A E, Yang Y, Cerniglia C E
National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA.
Appl Environ Microbiol. 1996 Mar;62(3):798-803. doi: 10.1128/aem.62.3.798-803.1996.
When tested as a microbial model for mammalian drug metabolism, the filamentous fungus Cunninghamella elegans metabolized chlorpromazine and methdilazine within 72 h. The metabolites were extracted by chloroform, separated by high-performance liquid chromatography, and characterized by proton nuclear magnetic resonance, mass, and UV spectroscopic analyses. The major metabolites of chlorpromazine were chlorpromazine sulfoxide (36%), N-desmethylchlorpromazine (11%), N-desmethyl-7-hydroxychlorpromazine (6%), 7-hydroxychlorpromazine sulfoxide (36%), N-hydroxychlorpromazine (11%), 7-hydroxychlorpromazine sulfoxide (5%), and chlorpromazine N-oxide (2%), all of which have been found in animal studies. The major metabolites of methdilazine were 3-hydroxymethdilazine (3%). (18)O(2) labeling experiments indicated that the oxygen atoms in methdilazine sulfoxide, methdilazine N-oxide, and 3-hydroxymethdilazine were all derived from molecular oxygen. The production of methdilazine sulfoxide and 3-hydroxymethdilazine was inhibited by the cytochrome P-450 inhibitors metyrapone and proadifen. An enzyme activity for the sulfoxidation of methdilazine was found in microsomal preparations of C. elegans. These experiments suggest that the sulfoxidation and hydroxylation of methdilazine and chlorpromazine by C. elegans are catalyzed by cytochrome P-450.
当作为哺乳动物药物代谢的微生物模型进行测试时，丝状真菌雅致小克银汉霉在72小时内代谢了氯丙嗪和甲硫哒嗪。代谢产物用氯仿提取，通过高效液相色谱分离，并用质子核磁共振、质谱和紫外光谱分析进行表征。氯丙嗪的主要代谢产物是氯丙嗪亚砜（36%）、N-去甲基氯丙嗪（11%）、N-去甲基-7-羟基氯丙嗪（6%）、7-羟基氯丙嗪亚砜（36%）、N-羟基氯丙嗪（11%）、7-羟基氯丙嗪亚砜（5%）和氯丙嗪N-氧化物（2%），所有这些在动物研究中都已发现。甲硫哒嗪的主要代谢产物是3-羟基甲硫哒嗪（3%）。（18）O2标记实验表明，甲硫哒嗪亚砜、甲硫哒嗪N-氧化物和3-羟基甲硫哒嗪中的氧原子均来自分子氧。甲硫哒嗪亚砜和3-羟基甲硫哒嗪的产生受到细胞色素P-450抑制剂美替拉酮和丙胺卡因的抑制。在雅致小克银汉霉的微粒体制剂中发现了甲硫哒嗪硫氧化酶活性。这些实验表明，雅致小克银汉霉对甲硫哒嗪和氯丙嗪的硫氧化和羟基化是由细胞色素P-450催化的。
