Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Buthionine sulfoximine (BSO), a specific inhibitor of glutathione synthesis, showed variable growth-inhibitory activity in different tumor cell lines with a high degree of inhibitory activity against melanoma-derived cell lines. A correlation between BSO growth-inhibitory effects and cellular glutathione peroxidase activity was observed. In contrast, no correlation was demonstrated between the response to BSO and cellular tyrosinase, gamma-glutamylcysteine synthetase, glutathione transferase, gamma-glutamyl transpeptidase, or glutathione reductase activities. BSO enhanced 3,4-dihydroxybenzylamine (3,4-DHBA) (fourfold) and melphalan (threefold) in vitro cytotoxic activity as determined by inhibition of DNA synthesis in human melanoma cells and this enhancement was dependent on the duration of exposure to drug. BSO demonstrated in vivo antitumor activity in B16 melanoma-bearing mice prolonging survival by 29% and in combination with 3,4-DHBA resulted in a slight (48% versus 38%) increase in life span as compared to 3,4-DHBA alone. The combination of BSO and melphalan, however, increased the life span of B16 melanoma-bearing mice by 170%, as compared to melphalan alone (80%). These studies demonstrate a unique in vivo antimelanoma activity of BSO.
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PMID:Melanoma cytotoxicity of buthionine sulfoximine (BSO) alone and in combination with 3,4-dihydroxybenzylamine and melphalan. 151 64

The aim of the present work was to estimate the effect of intracellular glutathione depletion on melanogenesis in human melanoma cells. We determined tyrosine hydroxylation activity, the rate-limiting step of the pathway, and 14C-melanin formation, an assay reflecting the global eumelanogenic pathway. Intracellular glutathione was depleted by treatment with buthionine-S-sulfoximine, a well-known inhibitor of gamma-glutamylcysteine synthetase. The intracellular depletion of glutathione was substantial after 20 h of incubation with 50 microM buthionine-S-sulfoximine, although a significant effect could be observed after 6 h. Tyrosine hydroxylase activity increased in parallel with glutathione depletion, to reach 160% with respect to the control values during 24 h of buthionine-S-sulfoximine treatment. We have found the response to buthionine-S-sulfoximine to be dose dependent and the two different human cell lines HBL and LND1 to have similar, if not identical, responses. 14C-melanin formation assay revealed even greater activation, up to 400% of the control values. This indicates that glutathione depletion may have two distinct effects: first, a direct one on tyrosinase activity and, second, an effect on the promotion of eumelanogenesis. The stimulation of tyrosine hydroxylase can be explained by a possible inactivation of the enzyme by endogenous thiol compounds rather than by a direct effect of buthionine-S-sulfoximine itself on tyrosinase. The data suggest that thiol compounds may play a role for stimulation of melanogenesis by ultraviolet radiation.
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PMID:Glutathione depletion increases tyrosinase activity in human melanoma cells. 790 81

Glutathione (GSH) performs several important biological functions, including quenching of reactive oxygen species, and protection of cells from toxic compounds such as quinones. The first step in the synthesis of GSH is catalysed by gamma-glutamylcysteine synthetase, an enzyme which is inhibited by cystamine and buthionine sulfoximine (BSO). In this study, we examined the possibility that the effect of hydroquinone (HQ) on pigmentation could be potentiated by inhibiting the production of GSH. In vitro studies using melanoma cell lines demonstrated that both cystamine and BSO could potentiate the inhibitory effects of HQ on tyrosinase activity and melanin content. A synergistic decrease in hair pigmentation was observed when a combination of HQ (2 or 4%) and BSO (5%) was applied to the dorsal skin of C57BL mice. In black hairless guinea-pigs, the application of HQ plus either BSO or cystamine resulted in a significant decrease in epidermal pigmentation when compared with any of the agents alone. The possibility exists that in the future a combination of HQ plus cystamine or BSO could be used to treat disorders such as melasma and post-inflammatory hyperpigmentation.
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PMID:Enhancement of the depigmenting effect of hydroquinone by cystamine and buthionine sulfoximine. 854 87

The catechol 5-S-cysteinyldopa (5-S-CD) is produced in large amounts in metastatic malignant melanoma. To further understand the mechanism of formation of 5-S-CD, we investigated the effects of thiol modulating agents and melanin precursors on human melanoma cells. Under standard culture conditions (0.1 mM cystine), the cell levels of 5-S-CD were highly correlated with the degree of melanization and the dopa oxidase activity of the four cell lines investigated (Me8, JUSO, GLL19, Swift). Inhibition of glutathione (GSH) biosynthesis with buthionine sulphoximine did not affect 5-S-CD levels in the low melanotic GL 19 cells. In contrast, the highly pigmented Swift cells showed a strong increase in the cell levels of cystine (CysH) and 5-S-CD. When the cystine concentration of the growth medium was increased to 0.2 mM, a similar situation of 5-S-CD synthesis caused by an increase in intracellular CysH levels was observed in the Swift cells. The GLL19 cells showed enhanced 5-S-CD formation in the presence of 0.1 mM L-dopa. This effect was associated with a fourfold increase in dopa oxidase activity. Our data clearly indicate that 5-S-CD is formed in human melanoma cells by a tyrosinase-dependent mechanism involving the addition of CysH to dopaquinone. Based on the enhancing effect of buthionine sulphoximine on 5-S-CD formation, it is proposed that GSH is not directly implicated in 5-S-CD formation, but regulates CysH levels via the enzyme gamma-glutamylcysteine synthetase.
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PMID:Modulation of 5-S-cysteinyldopa formation by tyrosinase activity and intracellular thiols in human melanoma cells. 881 21