Bioactivity and Use of Kojic Acid and Its Derivatives KX4 Molecules

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Used as an important material in antibiotic and pesticide productions kojic acid has been shown to act as a competitive and reversible inhibitor of animal and plant polyphenol oxidases, xanthine oxidase, and D- and some L-amino acid oxidases. Although kojic acid has been widely studied in the tumorigenic potential, genotoxic risk for humans and other applications, the mechanism of kojic acid on the gene expression and regulation in normal and/or diseased cells has rarely been studied. Recently a high throughput DNA microarray technique has an important role for genomics research by allowing the study of the function of thousands of genes simultaneously, showing differential gene expression profiling, and opening the door to the discovery the biomarkers or special gene markers that intend to use for pharmaceutical applications and disease therapy.

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In a study about the mechanism of kojic acid on the gene expression and regulation, Sun-Long CHENG et. al. used the DNA microarray technology to investigate the biological effects of kojic acid on the differential gene expression profiling of A375-malignant melanoma cells as a model of human skin cells in order to understand the genetic basis of metabolic and cellular responses to human skin and to discover the target- based drug of new genes leading to a systematic drug development approach.

In this study, they used the human skin A375 malignant melanoma cells to examine the genotoxicity effect of kojic acid on carcinoma therapy, except skin whitening effect.

To examine the genotoxicity effect of kojic acid on gene expression profiling of A375 cells, the microarray technology providing the high throughput method for easily screening the number of differentially expressed genes was used.

For the cell treatment, they examined the various concentrations (0.32, 1.6, 8, 40, 200, 1000m g/ml) of kojic acid on the growth inhibition of A375 cells. All of kojic acid concentrations did not strongly inhibit the cell growth of A375 cells even though the incubation time was longer (72 h). By using microarray technology to study the overall effects of kojic acid on whole gene expression of A375 cells, they used the kojic acid at the concentration of 8m g/ml (0.8%) because this is the mild concentration that could inhibit A375 cells with the inhibition less than 20% and avoid the differential gene expression data resulting from cell death response of cytotoxicity of high concentration of kojic acid.

Moreover, the safety of kojic acid for human skin care products is recommended for general use at a concentration up to 1% without prescription. Under this consideration, the concentration of 8m g/ml kojic acid (0.8%) is safe for human skin and can be used to study the gene expression profiling in A375 cells and through the regulatory functions of differentially expressed genes on carcinogenesis therapy. For the number of differentially expressed genes, they have selected the significant genes correlated to the carcinogenesis and also used RT-qPCR for validating gene expression changes, comparing microarray analysis data. Interestingly, we found seven significant kojic acid-responded genes that were down-regulated in kojic acid-stimulated A375 cells.

Most of genes are highly related to the regulation of carcinogenesis process. These genes are APOBEC1 (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1), ARHGEF16 (Rho guanine exchange factor (GEF) 16), CD22, GALNT1, UNC5C, FGFR3 (fibroblast growth factor receptor 3), human OZF gene. In addition, seven downregulated genes showed significantly differential expression in A375 cells after kojic acid treatment and played the function as tumor suppressors that may deactivate the regulation of melanoma tumorigenesis in human malignant melanoma cells. These genes may become the useful markers for further diagnostic and therapeutic applications (Sun-Long CHENG, 2006).

Although the toxicogenomics of kojic acid treated A375 human malignant melanoma cells has been elucidated, the proteomics of cellular response is still poorly understood. Although one gene makes one protein, the modifications of proteins leading to changes in biological and physiological functions may not be caused by gene modification. Sun-Long Cheng et.al performed proteomic analysis of continuation of their previous work, to investigate the anticancer effect of kojic acid on protein expression profile in A375 cells (Sun-Long Cheng, 2007). A375 cells were treated with kojic acid at 8 μg/mL for 24, 48, and 72 h. With the use of 2-D PAGE and MALDI-Q-TOF MS and MS/MS analyses, proteomic profiles of A375 cells between control and kojic acid treatment were compared, and 30 differentially expressed proteins, containing 2 up-regulated proteins and 28 down-regulated proteins, were identified.

Among these proteins, 17 isoforms of 5 identical proteins were observed and 11 chaperone proteins showed the high proportion of protein spots with 36.7% of total proteins. After 2-D PAGE, 30 differentially expressed proteins, showing the significant fold-change of protein expression level at 72 h treatment, were identified. They also used the combined databases to propose the protein interaction network, in which 16 differentially expressed proteins are correlated to the regulation of apoptosis via the major signaling proteins, such as p53, Ras, MEK/ERK, RAF-1 and Bcl-2. Interestingly, 11 chaperone proteins were down-regulated in kojic acid treated A375 cells and were found to be correlated by their interactions to each other. In cancer biology, heat shock proteins were found to express at high levels in facilitate tumor cell growth and survival.

According to their results of down-regulated heat shock proteins in kojic acid treated A375 cells, the cellular stress of the malignant melanoma cells occurred under kojic acid treatment. Kojic acid could suppress the expression of heat shock proteins, which support the tumor growth, and may lead to antiapoptosis effect. The suppression of heat shock protein expression by kojic acid may play an important role in the antitumor activity.

According to 2-D gel images, 6 isoforms of vimentin were down-regulated in kojic acid-treated A375 cells. Interestingly, their proposed interaction network revealed the correlated proteins with the regulation of apoptosis, which may lead to suppress the melanogenesis and tumorigenesis of cancer cells. Moreover, these proteins may be the useful biomarkers for further uses in diagnostic and therapeutic applications of skin cancer. However, further functional study of these proteins may lead to better understanding of the pathogenic mechanisms and cellular response to kojic acid treatment (Sun-Long Cheng, 2007).

A complex genotoxic profile of KA has been reported; however, it is still unclear whether or not KA is a genotoxic carcinogen. Although there is no report that positive results were obtained in genotoxic carcinogens using the same protocol as that in the present study, Cater et al. (1985) reported the formation of GGT-positive foci and liver tumors in newborn mice which were administered dimethylnitrosamine and PB as an initiator and a promoter, respectively. It is generally considered that carcinogenesis is initiated by DNA or chromosomal lesions, these lesions are fixed, and these then progress to the next step such as proliferation or differentiation. Therefore, it can be considered that genotoxicity is closely related to tumorinitiating activities. Regarding the genotoxicity of KA, many in vitro and in vivo studies have been preformed.

In the Ames test, KA presents positive results in S. typhimurium TA100, TA1535 and TA98 strains and in E. coli WP2uvrA at =2,000–1,000 lg/plate and =1,000 lg/ plate with and without S9 mix fraction, respectively, although negative results were obtained in TA1537 and TA1538 strains (Nohynek et al. 2004; Shibuya et al. 1982; Wei et al. 1991). In in vitro studies on DNA damage, positive and negative results were obtained in the rec-assay and SOS stop test respectively (Manabe et al. 1981). Positive results were obtained at the concentration of =1000 mg/ mL in studies on the detection of chromosomal aberrations and sister chromatid exchanges in CHO and Chinese hamster V79 cells (Nohynek et al. 2004; Wei et al. 1991; Auffaray and Boutibonnes 1986).

However, most of the positive results were accompanied by cytotoxicity (Nohynek et al. 2004). In order to evaluate the tumor-initiating activity of kojic acid (KA) in mouse liver, an in vivo initiation assay in liver was performed using partially hepatectomized mice by Mitsuyoshi Moto et. al. Male ICR mice were fed on a basal diet (BD) containing 0 or 3% KA for 4 weeks, followed by distilled water (DW) containing 0 or 500 ppm phenobarbital (PB) for 13 weeks. In microscopic examinations, no proliferative lesion was observed in any of the groups. There were no differences in the number of c-glutamyltransferase-positive cells, an expected marker for preneoplastic hepatocytes in mice, between the KA + DW and the KA + PB groups.

In the immunohistochemical analyses of the proliferating activity of hepatocytes, significant increases in the labeling index of proliferating cell nuclear antigen (PCNA) were observed in the BD+PB and KA + PB groups as compared to the BD + DW group; however, no significant difference in the positivity of PCNA was observed between the BD + PB and the KA + PB groups. These results of the present study suggest the possibility that KA has no tumor-initiating activity in the liver of mice. In conclusion, their experiments in mice suggest that treatment with a diet containing 3% KA for 4 weeks does not show any tumor-initiating activity, but has a hepatocarcinogenic potential. It is considered that further studies such as the evaluation of tumor-promoting activity are necessary to clarify the mechanism of hepatocarcinogenesis induced by KA (Mitsuyoshi Moto, 2006).