Structure-activity relationship of antioxidants for inhibitors of linoleicacid hydroperoxide-induced toxicity in cultured human umbilical vein endothelial cells

Structure-activity relationship of antioxidants for the protective effects on linoleic acid hydroperoxide (LOOH)-induced toxicity were examined in cul tured human umbilical vein endothelial cells. alpha -Tocopherol, 2,2,5,7,8- pentamethylchroman-6-ol, butylated hydroxytoluene, probucol, and fatty acid esters of ascorbic acid provided efficient protection against the cytotoxi city of LOOH in pretreatment, but phenols without alkyl groups at the ortho positions and hydrophilic antioxidants such as Trolox and ascorbic acid pr ovided no protection. Probably, the effectiveness of the protection against cytotoxicity by these antioxidants depends primarily on their rate of inco rporation into cells due to their lipophilicity, secondly on their antioxid ant activity, and thirdly on their orientation in biomembranes. On the othe r hand, flavones, such as baicalein and luteolin bearing 3 to 5 hydroxyl gr oups, and flavonols showed a protective effect against LOOH cytotoxicity wh en added together with LOOH, but not by pretreatment. Among catechins, (+)- catechin and (-)-epigallocatechin gallate monoglucoside and diglucoside wer e effective in suppressing LOOH-induced cytotoxicity, but their effects wer e not so strong. The structure-activity relationship of flavonoids revealed the presence of either the ortho-dihydroxy structure in the B ring of flav onoids or the 3-hydroxyl and 4-oxo groups in the C ring to be important for the protective activities. Furthermore, coumarins such as esculetin contai ning the ortho catechol structure had protective effects in both pretreatme nt and concurrent treatment. These results suggest that ortho catechol moie ty of flavonoids, catechins, and coumarins is an important structure in the protection against LOOH-induced cytotoxicity, and that the alkyl groups of monophenols are critical for protection.