PMID- 25768656
OWN - NLM
STAT- MEDLINE
DCOM- 20160122
LR  - 20150420
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 28
IP  - 4
DP  - 2015 Apr 20
TI  - 7-glutathione pyrrole adduct: a potential DNA reactive metabolite of 
      pyrrolizidine alkaloids.
PG  - 615-20
LID - 10.1021/tx500417q [doi]
AB  - Pyrrolizidine alkaloid (PA)-containing plants are the most common poisonous 
      plants affecting livestock, wildlife, and humans. PAs require metabolic 
      activation to form pyrrolic metabolites to exert cytotoxicity and tumorigenicity. 
      We previously determined that metabolism of tumorigenic PAs produced four DNA 
      adducts, designated as DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, that are 
      responsible for liver tumor initiation. 
      7-Glutathione-(+/-)-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine (7-GS-DHP), formed 
      in vivo and in vitro, and 7,9-di-GS-DHP, formed in vitro, are both considered 
      detoxified metabolites. However, in this study we determined that incubation of 
      7-GS-DHP with 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) yields DHP-dG-3, 
      DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts as well as the reactive metabolite DHP. 
      Furthermore, reaction of 7-GS-DHP with calf thymus DNA in aqueous solution at 37 
       degrees C for 4, 8, 16, 24, 48, or 72 h, followed by enzymatic hydrolysis yielded 
      DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts. Under our current 
      experimental conditions, DHP-dA-3 and DHP-dA-4 adducts were formed in a trace 
      amount from the reaction of 7,9-di-GS-DHP with dA. No DHP-dG-3 or DHP-dG-4 
      adducts were detected from the reaction of 7,9-di-GS-DHP with dG. This study 
      represents the first report that the 7-GS-DHP adduct can be a potential reactive 
      metabolite of PAs leading to DNA adduct formation.
FAU - Xia, Qingsu
AU  - Xia Q
AD  - daggerNational Center for Toxicological Research, U.S. Food and Drug Administration, 
      Jefferson, Arkansas 72079, United States.
FAU - Ma, Liang
AU  - Ma L
AD  - daggerNational Center for Toxicological Research, U.S. Food and Drug Administration, 
      Jefferson, Arkansas 72079, United States.
FAU - He, Xiaobo
AU  - He X
AD  - daggerNational Center for Toxicological Research, U.S. Food and Drug Administration, 
      Jefferson, Arkansas 72079, United States.
FAU - Cai, Lining
AU  - Cai L
AD  - double daggerBiotranex LLC, Monmouth Junction, New Jersey 08852, United States.
FAU - Fu, Peter P
AU  - Fu PP
AD  - daggerNational Center for Toxicological Research, U.S. Food and Drug Administration, 
      Jefferson, Arkansas 72079, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20150331
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (DNA Adducts)
RN  - 0 (Pyrroles)
RN  - 0 (Pyrrolizidine Alkaloids)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Chromatography, High Pressure Liquid
MH  - DNA Adducts/*chemistry
MH  - Glutathione/*chemistry
MH  - Pyrroles/*chemistry
MH  - Pyrrolizidine Alkaloids/*chemistry
EDAT- 2015/03/15 06:00
MHDA- 2016/01/23 06:00
CRDT- 2015/03/14 06:00
PHST- 2015/03/14 06:00 [entrez]
PHST- 2015/03/15 06:00 [pubmed]
PHST- 2016/01/23 06:00 [medline]
AID - 10.1021/tx500417q [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2015 Apr 20;28(4):615-20. doi: 10.1021/tx500417q. Epub 2015 Mar 
      31.