Up-regulation of the glutathione S-transferase system in human liver by polycyclic aromatic hydrocarbons; comparison with rat liver and lung

Abstract

The cytosolic glutathione S-transferases (GSTs) comprise a pivotal enzyme system protecting the cell from electrophilic compounds. It plays a major role in the detoxication of the primary and dihydrodiol epoxides of polycyclic aromatic hydrocarbons (PAHs), so that modulation of this enzyme system by PAHs will impact on their carcinogenic activity. The potential of six structurally diverse PAHs, namely benzo[a]pyrene (B[a]P), fluoranthene, benzo[b]fluoranthene (B[b]F), dibenzo[a,l]pyrene, dibenzo[a,h]anthracene (D[a,h]A) and 1-methhylphenanthrene, to modulate hepatic GST activity was investigated in human precision-cut slices and compared to rat slices, a species frequently used in long-term carcinogenicity studies; changes were monitored at the activity, using three different substrates, protein and mRNA levels. When activity was monitored using the alpha-class selective 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, B[b]F was the only PAH that caused an increase in activity, which was accompanied by a rise in the Ya immunoreacting band. In rat slices, in addition to B[b]F, B[a]P and D[a,h]A also enhanced activity, being paralleled with increased levels of the Ya immunoreacting band. In the rat, all PAHs elevated mRNA levels. In both human and rat liver slices, only B[b]F enhanced activity when 1-chloro-2,4-dinitrobenzene (CDNB) served as substrate. To investigate tissue differences, similar studies were undertaken in precision-cut rat lung slices, incubated with PAHs under identical conditions, using CDNB, as this was the only substrate for which activity could be detected; none of the PAHs studied stimulated activity. It is concluded that some PAHs have the potential to induce GST activity in human liver tissue and that species and tissue differences exist in the induction of this enzyme system in the rat. However, the extent of induction of GST activity is very modest compared with the effect these compounds have on CYP1 expression, the family responsible for their bioactivation, and it is unlikely to compensate for the enhanced production of reactive intermediates.

Silymarin prevents benzo(a)pyrene-induced toxicity in Wistar rats by modulating xenobiotic-metabolizing enzymes

“…The isoforms GSTP1 and GSTM1 catalyzes the conjugation of reactive B(a)P metabolites with the nucleophilic thiol group of GSH (Hayes and Pulford, 1995) and suppress the B(a)P-induced adduct formation (Sundberg et al, 1997). It has been already emphasized that GST is induced to a greater extent in rat liver than human liver during B(a)P treatment (Pushparajah et al, 2008). In the present study, GST was increased by 1.5 fold in animals treated with B(a)P, when compared to the controls.…”

Enhanced tolerance and remediation of anthracene by transgenic tobacco plants expressing a fungal glutathione transferase gene

“…The cytosolic glutathione-s-transferase comprises a pivotal enzyme system for protecting the cell from electrophilic compounds and is known to play a major role in detoxification of xenobiotics [17]. Polycyclic aromatic hydrocarbons are known to induce GSTs in human liver [31]. Heterologous expression of GSTs in plants is expected to mediate degradation of xenobiotics [8].…”

Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced Toxicity

“…A, scores plot of a PCA model on 24-h urine samples from the preinjection control and after APAP injection of AP2, AP4, APR2, and APR4 group mice. A two-component PCA model was constructed to characterize the relationship among eight mouse groups (3-4 mice/ group), including the preinjection control of AP2 ‚, AP4 छ, APR2 ƒ, and APR4 E and after APAP injection of AP2 OE, AP4 ࡗ, APR2 , and APR4 reduced toxicity (Pushparajah et al, 2008). Thus, it is likely that the GST induction observed is a protective mechanism that occurs in response to xenobiotic exposure due to PXR activation.…”