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  • The present studies show that despite the

    2022-05-18

    The present studies show that, despite the high level of GSTP1-1 achieved in transfected cells, GSTP1-1 expression has no effect on sensitivities to the cytotoxicities of the oxazaphosphorines 4-OH-CP, 4-OOH-CP, and maf in MCF7 ODQ (Fig. 4). The failure of GSTP1-1 to augment resistance indicates that either: 1) the formation of glutathione conjugates is only a minor mechanism of oxazaphosphorine detoxification; or 2) at the level of intracellular metabolites formed, non-enzymatic conjugation with glutathione is more important than GSTP1-1-catalyzed detoxification. However, the finding that MRP alone confers some resistance raises the possibility that toxic metabolites of oxazaphosphorines, which may include glutathione conjugates, are substrates for MRP-associated export. Cisplatin is an interesting model compound to test for GSTP1-1/MRP-associated resistance. On the one hand, increased MRP is not generally associated with cisplatin resistance 53, 54, and GSTP1-1 has not been shown to catalyze chemical transformations of cisplatin. However, some laboratories have reported an association between increased GSTP1-1 and cisplatin resistance 31, 32. Additionally, cisplatin can form complexes with glutathione [27] that are potential substrates of MRP or related transporter proteins 15, 29, 30. Indeed, Ishikawa et al. [29] reported findings that suggested that increased MRP expression can be associated with cisplatin resistance. Moreover, they found that glutathione conjugates of cisplatin can inhibit MRP-mediated transport of labeled leukotriene C4—results indicating that platinum–glutathione complexes may be substrates of MRP. Our data clearly show that relatively high level GSTP1-1 expression had no effect on the cisplatin sensitivity of MCF7 cells regardless of their MRP status (Fig. 5, A and B). In contrast, MRP confers a very modest but statistically significant resistance to cisplatin in MCF7/VP cells (Fig. 5C). These data are consistent with the findings of Ishikawa et al. [29] and suggest at least a limited role for MRP in some forms of cisplatin resistance.
    Acknowledgements
    Introduction Patients with prescriptions higher than − 6.00 D or an axial length above 26 mm are defined as high myopes and tend to develop rapid, progressive nuclear cataracts with a higher grade than normal people [1], [2], [3]. Based on the latest data on vision screening and demographic census, it is estimated that there are currently at least three hundred million patients with high myopia worldwide, especially in East Asia [4], [5], [6]. Accordingly, highly myopic cataracts (HMCs) are more frequently observed with the rapidly growing incidence of high myopia. In normal eyes, the posterior surface of the lens is separated from the inner surface of the retina by an intact vitreous body, which helps preserve the low-oxygen environment surrounding the lens [7]. However, in highly myopic eyes, vitreous gel degeneration occurs much earlier and on a greater scale than in nonmyopic eyes [8], possibly subjecting the lens to higher concentrations of O2. Elevated oxidative stress may then induce damage to the lens epithelial cells (LECs), the center of normal lens metabolism, and consequently lead to lens opacity. Our previous study found that the promoter of the CRYAA gene, encoding a major structure protein, αA- crystallin, in the lens, is hypermethylated and hence downregulated in the lens of HMC patients, which could be one of the mechanisms that explains the higher severity of cataracts in highly myopic eyes [3], [9]. In addition to being a structural crystallin, αA- crystallin is also a molecular chaperone with a known function in preventing oxidative damages. These findings prompted us to explore other important antioxidant genes in HMC with the aim of expanding our understanding of this antioxidant system. To further investigate the underlying epigenetic etiology of HMC, we chose six essential oxidative stress related genes according to previous reports [10], [11], [12], [13], [14]: glutathione S- transferase pi 1 (GSTP1), nuclear factor, erythroid like 2 (NRF2), 8-oxoguanine DNA glycosylase (OGG1), thioredoxin (TXN), thioredoxin reductase 1 (TXNRD1) and thioredoxin reductase 2 (TXNRD2). Among these six genes, the expression of GSTP1 has been recently reported to be downregulated in the lens epithelium and cortex of age-related cataracts (ARCs) due to epigenetic alterations, including the hypermethylation of its promoter [15]. Another study showed significantly lower protein and gene expression levels of NRF2 in lenses of increasing age [16]. Furthermore, Nrf2 is a known target for preventing ARC by acting against oxidative stress [17]. OGG1 plays a vital role in DNA repair in response to oxidative stress, the mRNA and protein levels of OGG1 were also significantly reduced in the lens cortex of ARC [18], [19]. Furthermore, the CpG islands in the first exon of OGG1 are hypermethylated in the DNA from the lens cortex of ARC [18]. As oxidation defense enzymes functioning in the lens, TXN and TXNRD1 have also been reported to be upregulated under oxidative stress [20].