A putative cellular function of tetrahydropteridines (L L-erythro-tetrahydrobiopterin and D D-threo-tetrahydrobiopterin) was investigated in Dictyostelium discoideum Ax2 using a mutant disrupted in the gene encoding sepiapterin reductase (SR). The SR mutant, which produces about 3% of tetrahydropteridines if compared to wild-type, was elucidated to have several functional defects related to mitochondria and oxidative stress: retarded growth, poor spore viability, impaired mitochondrial function, and increased susceptibility to oxidative stress induced by hydroxylamine or cumene-hydroperoxide. However, the physiological defects were almost completely rescued by extrachromosomal expression of Dictyostelium SR. The results strongly suggested that tetrahydropteridines in Dictyostelium are associated with mitochondrial function, probably via direct protection against oxidative stress.

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Background: Phenolic compounds EGCG [(–)-epigallocatechin-3-gallate], resveratrol (3,4′,5-trihydroxy-trans-stilbene) and capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) are worth investigating for clinical application in cancer prevention and chemotherapy. Hypoxia-induced drug resistance is a major obstacle in the development of effective cancer chemotherapy. Therefore, we examined whether drug resistance to these phenolic compounds is acquired by hypoxia. Methods: Hep3B hepatoma, Caki-1 renal carcinoma, SK-N-MC neuroblastoma, and HEK293 cell lines were cultured under normoxic or hypoxic conditions. Drug sensitivities to the phenolic compounds and expression of hypoxia-inducible factor-1α (HIF-1α) and the multidrug resistance genes were examined in these cell lines. Results: Drug resistance was acquired 24 h after hypoxia and subsided 8 h after reoxygenation. Protein synthesis inhibitors abolished this drug resistance. A transfection study demonstrated that HIF-1α enhanced this hypoxia-induced resistance and that its dominant-negative isoform suppressed resistance acquisition. However, MDR1 and MRP1, which provide multidrug resistance to conventional anticancer agents, were not induced by hypoxia. Conclusions: These results suggest that HIF-1α-dependent gene expression participates in the cellular process of the hypoxia-induced resistance to phenolic compounds.

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