The developmental expression of alpha-, mu- and pi-class glutathione S-transferases in human liver

Strange, Richard C.; Howie, A F; Hume, Robert; Matharoo, B.; Bell, Jeanne E.; Hiley, Christopher; Jones, Peter W.; Beckett, Geoffrey J.

doi:10.1016/0304-4165(89)90162-1

Cited by 72 publications

(39 citation statements)

References 14 publications

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“…Both prenatal and postnatal livers possess good but variable activities for 1-chloro-2,4-dinitrobenzene, and a slight trend of increased activity was suggested with age. Detailed ontogenic information for specific GST members is available only from a study by Strange et al (1989) on A, M, and P classes. The developmental pattern of Z1 is most similar to those of A1, A2, and M classes for a progressive increase with age, which is the reverse of that observed with the P class.…”

Section: Et Almentioning

confidence: 99%

“…The GSTZ1 enzyme is distinct from other classes in that it exhibits a near-baseline level in the fetus and a developmental onset beginning in the neonatal period. In adults, hepatic GSTZ1 content (median, 0.48 g/mg cytosolic protein; range, 0.11-0.91; GSTZ1 molecular mass of 24 kD was used in conversion) is approximately 40-fold lower than that of GSTA1/A2, the most abundant cytosolic GSTs in postnatal livers with mean levels reported to be 16.5 g/mg cytosolic protein by Strange et al (1989) and 21.84 by Mulder et al (1994).…”

Section: Et Almentioning

confidence: 99%

“…Several GST classes (GSTA, GSTM, and GSTP) exhibit distinct changes in hepatic expression during human development (Strange et al, 1989). In this study, we investigated the roles of subject age and GSTZ1 haplotype in determining the expression and activity of GSTZ1 with DCA in human liver samples.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Gu²,

James³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Glutathione transferase 1 (GSTZ1), also known as maleylacetoacetate isomerase, catalyzes the penultimate step of tyrosine catabolism and metabolizes several ␣-halocarboxylic acids, including dichloroacetic acid (DCA), an investigational drug used for lactic acidosis and, recently, solid tumors. Age-related differences have been suggested in DCA pharmacotoxicology, but no information is available on GSTZ1 ontogeny in humans. Here, we investigated the cytosolic GSTZ1 developmental expression pattern and the influence of haplotype on GSTZ1 activity with DCA by using human livers from donors between 10 weeks gestation and 74 years. GSTZ1 expression was very low in fetal livers (<2 pmol of GSTZ1/mg cytosol). The expression began to increase after birth in an age-dependent manner until age 7 years. GSTZ1 was then sustained at stable, yet variable, levels (median, 20.0 pmol/mg cytosol; range, 4.8-47.3 pmol/mg cytosol) until age 74 years. GSTZ1 activity with DCA was strongly associated with haplotype and expression level. Samples homozygous or heterozygous for GSTZ1A exhibited ϳ3-fold higher DCA dechlorinating activity than samples carrying other alleles at a given level of expression. The correlations (r 2 ) between activity and expression were 0.90 and 0.68, respectively, for GSTZ1A carriers (n ‫؍‬ 11) and noncarriers (n ‫؍‬ 61). GSTZ1 is expressed in mitochondria in addition to cytosol. The GSTZ1A allele exhibited similar effects in the mitochondrial fraction by conferring a higher activity with DCA. In summary, we report a neonatal onset and an age-related increase in GSTZ1 protein expression during human liver development. Haplotype influenced GSTZ1 activity with DCA but not protein expression.

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Section: Et Almentioning

confidence: 99%

Section: Et Almentioning

confidence: 99%

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Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Gu²,

James³

et al. 2011

Drug Metab Dispos

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“…With the advent of specific immunological probes, more sophisticated studies were possible that allowed differentiation of the enzymes by GST class. Thus, using radioimmunological and immunohistochemical assays, Strange et al (1989) were able to detect hepatic GSTA1 (182.4 to 247.2 pmol/mg cytosol protein) and GSTA2 (14.2 to 31.2 pmol/mg cytosol protein) expression as early as 10-weeks gestation. GSTA1 and GSTA2 expression levels increased 1.5-to 4-fold, respectively, to adult levels within the first 1 to 2 years of life.…”

Section: Glutathione S-transferasementioning

confidence: 99%

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

McCarver¹,

Hines²

2002

J Pharmacol Exp Ther

323

151

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Changes in phase II drug-metabolizing enzyme expression during development, as well as the balance between phase I and phase II enzymes, can significantly alter the pharmacokinetics for a given drug or toxicant. Although our knowledge is incomplete, many of the phase II enzymes are expressed early in development. There is evidence for glutathione S-transferase A1/A2 (GSTA1/A2), GSTM, and GSTP1 in fetal liver, lung and kidney, although tissue-specific patterns and changes with time are observed. N-Acetyltransferase 1 (NAT1) activity also has been reported throughout gestation in fetal liver, adrenal glands, lung, kidney, and intestine. Only postnatal changes in NAT1 expression were apparent. Nothing is known about human NAT2 developmental expression. Some UDP-glucuronosyltransferase and sulfotransferase isoforms also are detectable in fetal liver and other tissues by the first or second trimester, and substantial changes in isoform expression patterns, as well as overall expression levels, are observed with increasing maturity. Finally, expression of both epoxide hydrolases 1 and 2 (EPHX1 and EPHX2) is observed in fetal liver, and for the former, increased expression with time has been documented. Less is known about ontogenic molecular control mechanisms. Limited data suggest that the hepatocyte nuclear factor and CCAAT/enhancer binding protein families are critical for fetal liver drug-metabolizing enzyme expression whereas D element binding protein and related factors may regulate postnatal hepatic expression. There is a paucity of data regarding mechanisms for the onset of extrahepatic fetal expression or specific mechanisms determining temporal switches, such as those observed within the CYP3A and flavin-containing monooxygenase families.Taking advantage of electrophilic functional groups already present on the molecule, or ones introduced during phase I metabolism, the phase II drug-metabolizing enzymes (DMEs) are characterized by their ability to conjugate xenobiotics using small molecular weight, organic donor molecules such as glutathione, UDP-glucuronic acid, or acetyl coenzyme A. These reactions generally result in pharmacological inactivation or detoxification, although instances of bioactivation are known. Conjugation products also can be substrates for specific transport enzymes, thus facilitating elimination from the body. Historically, research on DMEs has placed more emphasis on those catalyzing phase I versus phase II reactions. This also has been true with respect to studies on DME developmental expression. Given the importance of the conjugation enzymes in drug and toxicant disposition and, in particular, how the balance between phase I and phase II enzymes can dramatically alter pharmacokinetics and therefore therapeutic efficacy and/or xenobiotic toxicity, this area deserves increased attention.Advances in our understanding of phase II enzyme expression during ontogeny have been hampered by many of the same problems discussed for the phase I enzymes (Hines and McCarver, 2002). These ...

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“…Glutathione-S-transferases (GSTs) exist as multiple isoforms; of these, GST has been reported to be responsible for 50% of glutathione conjugation in fetal liver, but it regresses at birth and is not expressed in adults. Other classes of GST, including GSTμ and GST , are present in the fetal liver at low levels and increase after birth (Cresteil et al, 1982;Strange et al, 1989). Conjugation with glucuronic acid is significantly lower at birth than in adults, although the capability for conjugation with sulfate is well developed in neonates (Levy et al, 1975).…”

Section: Metabolic Characteristicsmentioning

confidence: 99%

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

Liu

Xia

Guo

et al. 2012

J Expo Sci Environ Epidemiol

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The urinary metabolites of phthalates are well-accepted exposure biomarkers for adults and children older than 6 years but are not commonly used for infants owing to non-convenient sampling. In the light of this situation, a novel sampling method based on monitoring the urine expressed from the gel diaper was developed. The urine was expressed from the gel absorbent after mixing the absorbent with CaCl2 and then collected by a laboratory-made device; the urinary phthalate metabolites were extracted and cleaned using a solid-phase extraction (SPE) column and analyzed with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry / mass spectrometry. To evaluate the method's feasibility, the following factors were investigated: the proportion of CaCl2 to gel absorbent, the urination volume variation and the target compounds' deposition bias in the diaper, the matrix blank of the different diaper brands, the storage stabilities and the recoveries of creatinine and phthalate metabolites in the expressed urine. Mono-methyl phthalate, mono-ethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, mono-2-ethylhexyl phthalate and mono-2-ethyl-5-oxohexyl phthalate were involved. 70-80% of the urine can be expressed from the diaper, and the expressed spiking recoveries and the limit of detection of mono-phthalates ranged from 88.5-115% and 0.21-0.50 ng/ml. The method was applied to measure phthalate metabolites in 65 gel diaper samples from 15 infants, and the pilot data suggests the infants are commonly exposed to phthalates. In summary, the method for monitoring of infant exposure to phthalates is sound and validated, and the potential health effects from the vulnerable infants' exposure to phthalates should be concerned.39th Scientific Research Foundation for the Returned Overseas Chinese Scholars (SRF for ROCS); Hundred Talent Program of Chinese Academy of Sciences (CAS); CAS/SAFEA International Partnership Program for Creative Research Teams [KZCX2-YW-T08

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The developmental expression of alpha-, mu- and pi-class glutathione S-transferases in human liver

Cited by 72 publications

References 14 publications

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

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