Reaction of Dehydropyrrolizidine Alkaloids with Valine and Hemoglobin

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• 作者：Yuewei Zhao ; Shuguang Wang ; Qingsu Xia ; Gon莽alo Gamboa da Costa ; Daniel R. Doerge ; Lining Cai ; Peter P. Fu
• 刊名：Chemical Research in Toxicology
• 出版年：2014
• 出版时间：October 20, 2014
• 年：2014
• 卷：27
• 期：10
• 页码：1720-1731
• 全文大小：703K
• ISSN：1520-5010

文摘

Pyrrolizidine alkaloid-containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids exert toxicity through metabolism to dehydropyrrolizidine alkaloids that bind to cellular protein and DNA, leading to hepatotoxicity, genotoxicity, and tumorigenicity. To date, it is not clear how dehydropyrrolizidine alkaloids bind to cellular constituents, including amino acids and proteins, resulting in toxicity. Metabolism of carcinogenic monocrotaline, riddelliine, and heliotrine produces dehydromonocrotaline, dehyroriddelliine, and dehydroheliotrine, respectively, as primary reactive metabolites. In this study, we report that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived valine (DHP鈥搗aline) adducts. For structural elucidation, DHP鈥搗aline adducts were derivatized with phenyl isothiocyanate (PITC) to DHP鈥搗aline鈥揚ITC products. After HPLC separation, their structures were characterized by mass spectrometry, UV鈥搗isible spectrophotometry, ¹H NMR, and ¹H鈥?sup>1H COSY NMR spectral analysis. Two DHP鈥搗aline鈥揚ITC adducts, designated as DHP鈥搗aline鈥揚ITC-1 and DHP鈥搗aline鈥揚ITC-3, had the amino group of valine linked to the C7 position of the necine base, and the other two DHP鈥搗aline鈥揚ITC products, DHP鈥搗aline鈥揚ITC-2 and DHP鈥搗aline鈥揚ITC-4, linked to the C9 position of the necine base. DHP鈥搗aline鈥揚ITC-1 was interconvertible with DHP鈥搗aline鈥揚ITC-3, and DHP鈥搗aline鈥揚ITC-2 was interconvertible with DHP鈥搗aline鈥揚ITC-4. Reaction of dehydroriddelliine and dehydroheliotrine with valine provided similar results. However, reaction of valine and dehydroretronecine (DHR) under similar experimental conditions did not produce DHP鈥搗aline adducts. Reaction of dehydromonocrotaline with rat hemoglobin followed by derivatization with PITC also generated the same four DHP鈥搗aline鈥揚ITC adducts. This represents the first full structural elucidation of protein conjugated pyrrolic adducts formed from reaction of dehydropyrrolizidine alkaloids with an amino acid (valine). In addition, it was found that DHP鈥搗aline-2 and DHP鈥搗aline-4, with the valine amino group linked at the C7 position of the necine base, can lose the valine moiety to form DHP.