Abstract:
:Glutathione S-transferase P1-1 (GSTP) is one member of the family of GSTs and is ubiquitously expressed in human tissues. The literature is replete with reports of high levels of GSTP linked either with cancer incidence or drug resistance, and yet no entirely cogent explanation for these correlations exists. The catalytic detoxification properties of the GST isozyme family have been a primary research focus for the last four decades. However, it has become apparent that they have undergone structural and functional convergence where evolutionary selective pressures have favored the emergence of noncatalytic properties of GSTP that has imbued this isozyme with expanded biological importance. For example, GSTP has now been linked with two cell-signaling functions that are critical to survival. Through protein:protein interactions, GSTP can sequester c-jun N-terminal kinase (JNK) and act as a negative regulator of this stress kinase. Pharmacologically, this activity has been linked with the activity of GSTP inhibitors in stimulating myeloproliferation. In addition, GSTP is linked with the forward S-glutathionylation reaction, a post-translational modification that impacts the function/activity of a number of proteins. Catalytic reversal of S-glutathionylation is well characterized, but the role of GSTP in catalyzing the forward reaction contributes to the "glutathionylation cycle." Moreover, GSTP is itself susceptible to S-glutathionylation, providing an autoregulatory loop for the cycle. Because oxidative stress regulates both S-glutathionylation and JNK-signaling pathways, such links may help to explain the aberrant patterns of GSTP expression in the cancer phenotype. As such, there is an ongoing preclinical and clinical platform of drug discovery and development around GSTP.
journal_name
Drug Metab Revjournal_title
Drug metabolism reviewsauthors
Tew KD,Townsend DMdoi
10.3109/03602532.2011.552912subject
Has Abstractpub_date
2011-05-01 00:00:00pages
179-93issue
2eissn
0360-2532issn
1097-9883journal_volume
43pub_type
杂志文章,评审abstract::Cytochrome P450 (CYP) 2D6 is one of the most important enzymes involved in the metabolism of drugs. Multiple, clinically relevant, genetic variants of this gene have been identified and, among them, a gene deletion as well as multiplications of the gene. These large structural mutations in CYP2D6 occur at a relatively...
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pub_type: 杂志文章,评审
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