Chemometric analysis of biofluids following toxicant induced hepatotoxicity: A metabonomic approach to distinguish the effects of 1-naphthylisothiocyanate from its products

被引:25
作者
Azmi, J
Griffin, JL
Shore, RF
Holmes, E
Nicholson, JK
机构
[1] Univ Cambridge, Dept Biochem, Cambridge CB2 4EW, England
[2] Univ London Imperial Coll Sci Technol & Med, Div Biomed Sci, Sect Biol Chem, London, England
[3] CEH Monks Wood, Huntingdon, England
关键词
1-nitronaphthalene; 1-naphthylamine; metabonomics; pattern recognition;
D O I
10.1080/00498250500297940
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Metabonomics using high-resolution H-1-NMR spectroscopy of biofluids and pattern recognition is highly successful at distinguishing both organ- and sub-organ-specific toxicity. In the current study, this technique was investigated to distinguish the different biological effects caused by 1-naphthylisothiocyanate (ANIT)-induced hepatotoxicity in the rat from that induced by exposure to 1-naphthylisocyanate (NI) and 1-naphthylamine (NA), two products of the metabolism of ANIT. While all three toxicants produced perturbations in similar urinary metabolites, principal components analysis of the temporal progression identified that the rapid initial glycosuria associated with ANIT toxicity was also present with NI but not NA dosing. However, longer-term perturbations in the urinary excretion of succinate, lactate and acetate were common to all three toxicants. The metabolic effects of the three compounds were also followed in blood plasma and liver tissue. Of the three toxicants, the most marked perturbations were induced by ANIT exposure, then NI, thereby indicating the effects of ANIT, NI and NA toxicity were distinct, with ANIT being the most, and NA the least, toxic of the three compounds. This indicates that metabonomics may be useful for following severity and mechanisms of toxicity in a series of related compounds during drug development.
引用
收藏
页码:839 / 852
页数:14
相关论文
共 20 条
[1]  
ANTHONY ML, 1994, MOL PHARMACOL, V46, P199
[2]   Metabolic trajectory characterisation of xenobiotic-induced hepatotoxic lesions using statistical batch processing of NMR data [J].
Azmi, J ;
Griffin, JL ;
Antti, H ;
Shore, RF ;
Johansson, E ;
Nicholson, JK ;
Holmes, E .
ANALYST, 2002, 127 (02) :271-276
[3]   PLATELETS AND ALPHA-NAPHTHYLISOTHIOCYANATE-INDUCED LIVER-INJURY [J].
BAILIE, MB ;
PEARSON, JM ;
LAPPIN, PB ;
KILLAM, AL ;
ROTH, RA .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1994, 129 (02) :207-213
[4]   Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins [J].
Beckwith-Hall, BM ;
Nicholson, JK ;
Nicholls, AW ;
Foxall, PJD ;
Lindon, JC ;
Connor, SC ;
Abdi, M ;
Connelly, J ;
Holmes, E .
CHEMICAL RESEARCH IN TOXICOLOGY, 1998, 11 (04) :260-272
[5]   INVOLVEMENT OF GLUTATHIONE IN 1-NAPHTHYLISOTHIOCYANATE (ANIT) METABOLISM AND TOXICITY TO ISOLATED HEPATOCYTES [J].
CARPENTERDEYO, L ;
MARCHAND, DH ;
JEAN, PA ;
ROTH, RA ;
REED, DJ .
BIOCHEMICAL PHARMACOLOGY, 1991, 42 (11) :2171-2180
[6]   PROTECTION AGAINST ALPHA-NAPHTHYLISOTHIOCYANATE-INDUCED LIVER-INJURY BY DECREASED HEPATIC NONPROTEIN SULFHYDRYL CONTENT [J].
DAHM, LJ ;
ROTH, RA .
BIOCHEMICAL PHARMACOLOGY, 1991, 42 (06) :1181-1188
[7]   Mechanisms of isocyanate sensitisation. An in vitro approach [J].
Elms, J ;
Beckett, PN ;
Griffin, P ;
Curran, AD .
TOXICOLOGY IN VITRO, 2001, 15 (06) :631-634
[8]   Cholestasis induced by chronic treatment with α-naphthyl-isothiocyanate (ANIT) affects rat renal mitochondrial bioenergetics [J].
Ferreira, FM ;
Oliveira, PJ ;
Rolo, AP ;
Santos, MS ;
Moreno, AJ ;
da Cunha, MF ;
Seiça, R ;
Palmeira, CM .
ARCHIVES OF TOXICOLOGY, 2003, 77 (04) :194-200
[9]  
GOLDFARB STANLEY, 1962, AMER JOUR PATHOL, V40, P685
[10]  
Holmes E, 1998, NMR BIOMED, V11, P235, DOI 10.1002/(SICI)1099-1492(199806/08)11:4/5<235::AID-NBM507>3.0.CO