PMID- 24308637
OWN - NLM
STAT- MEDLINE
DCOM- 20150123
LR  - 20190104
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 27
IP  - 1
DP  - 2014 Jan 21
TI  - Lack of metabolic activation and predominant formation of an excreted metabolite 
      of nontoxic platynecine-type pyrrolizidine alkaloids.
PG  - 7-16
LID - 10.1021/tx4004159 [doi]
AB  - Pyrrolizidine alkaloid (PA) poisoning is well-known because of the intake of 
      PA-containing plant-derived natural products and PA-contaminated foodstuffs. 
      Based on different structures of the necine bases, PAs are classified into three 
      types: retronecine, otonecine, and platynecine type. The former two type PAs 
      possessing an unsaturated necine base with a 1,2-double bond are hepatotoxic due 
      to the P450-mediated metabolic activation to generate reactive pyrrolic ester, 
      which interacts with cellular macromolecules leading to toxicity. With a 
      saturated necine base, platynecine-type PAs are reported to be nontoxic and their 
      nontoxicity was hypothesized to be due to the absence of metabolic activation; 
      however, the metabolic pathway responsible for their nontoxic nature is largely 
      unknown. In the present study, to prove the absence of metabolic activation in 
      nontoxic platynecine-type PAs, hepatic metabolism of platyphylline (PLA), a 
      representative platynecine-type PA, was investigated and directly compared with 
      the representatives of two toxic types of PAs in parallel. By determining the 
      pyrrolic ester-derived glutathione conjugate, our results confirmed that the 
      major metabolic pathway of PLA did not lead to formation of the reactive pyrrolic 
      ester. More interestingly, having a metabolic rate similar to that of toxic PAs, 
      PLA also underwent oxidative metabolisms mediated by P450s, especially P450 3A4, 
      the same enzyme that catalyzes metabolic activation of two toxic types of PAs. 
      However, the predominant oxidative dehydrogenation pathway of PLA formed a novel 
      metabolite, dehydroplatyphylline carboxylic acid, which was water-soluble, 
      readily excreted, and could not interact with cellular macromolecules. In 
      conclusion, our study confirmed that the saturated necine bases determine the 
      absence of metabolic activation and thus govern the metabolic pathway responsible 
      for the nontoxic nature of platynecine-type PAs.
FAU - Ruan, Jianqing
AU  - Ruan J
AD  - School of Biomedical Sciences, Faculty of Medicine, The Chinese University of 
      Hong Kong , Hong Kong SAR.
FAU - Liao, Cangsong
AU  - Liao C
FAU - Ye, Yang
AU  - Ye Y
FAU - Lin, Ge
AU  - Lin G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131213
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Heterocyclic Compounds, 2-Ring)
RN  - 0 (Pyrrolizidine Alkaloids)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - QLU72L7VMN (platynecine)
SB  - IM
MH  - Animals
MH  - Chromatography, High Pressure Liquid
MH  - Cytochrome P-450 Enzyme System/chemistry/metabolism
MH  - Heterocyclic Compounds, 2-Ring/chemistry/*metabolism
MH  - Humans
MH  - Microsomes, Liver/enzymology/metabolism
MH  - Molecular Structure
MH  - Pyrrolizidine Alkaloids/chemistry/*metabolism
MH  - Rats
MH  - Tandem Mass Spectrometry
EDAT- 2013/12/07 06:00
MHDA- 2015/01/24 06:00
CRDT- 2013/12/07 06:00
PHST- 2013/12/07 06:00 [entrez]
PHST- 2013/12/07 06:00 [pubmed]
PHST- 2015/01/24 06:00 [medline]
AID - 10.1021/tx4004159 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2014 Jan 21;27(1):7-16. doi: 10.1021/tx4004159. Epub 2013 Dec 
      13.