Inhibitory effects of 2-O-octadecylascorbic acid and other vitamin C and E derivatives on the induction of enzyme-altered putative preneoplastic lesions in the livers of rats fed a choline-deficient, L-amino acid-defined diet

Abstract

Effects of a lipophilic derivative of vitamin C, 2-O-octadecylascorbic acid (CV-3611), as well as its parent L-ascorbic acid (AscA), DL-alpha-tocopherol (alpha-T) and its hydrophilic derivative, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), on the number and size of gamma-glutamyltransferase (GGT)-positive putative preneoplastic lesions were examined and compared with their influences on 8-hydroxyguanine formation in DNA and 2-thiobarbituric acid-reacting substance generation in the livers of rats fed a choline-deficient, L-amino acid-defined (CDAA) diet for 12 weeks. A total of 90 male Fischer 344 rats, 6 weeks old, were divided into 18 groups each consisting of five rats. Group 1 received the CDAA diet alone; Groups 2, 3 and 4 received the CDAA diet containing respectively 0.01, 0.05 and 0.10% CV-3611; Groups 5-7, 8-10 and 11-13 similarly received the CDAA diet containing AscA, alpha-T and Trolox, respectively, at these same low, middle and high concentrations; Group 14 received a choline-supplemented, L-amino acid-defined (CSAA) diet alone; Groups 15-18 were given the CSAA diet containing CV-3611, AscA, alpha-T and Trolox, respectively, all at the 0.10% level. While all four vitamin derivatives exerted inhibitory effects on all four parameters, in each case dose-dependently, CV-3611 demonstrated the most pronounced effects. The present results indicated that lipophilic vitamin C derivatives may be particularly effective chemopreventive agents against CDAA diet-associated, oxidative stress-related hepatocarcinogenesis via its superior antioxidative properties.

Comparative Changes in the Liver of Female Fischer-344 Rats after Short-Term Feeding of a Semipurified or a Semisynthetic L-Amino Acid-Defined Choline-Deficient Diet

“…Recently, the resistance of female Fischer-344 rats toward induction of a high degree of compensatory mitogenesis and eventual tumorigenesis was found to be not absolute, but a function of the severity of the dietary lipotrope deficiency, because it was overcome by feeding a diet devoid of methionine, folic acid, and vitamin B12, as well as of choline (29 (12,19,(24)(25)(26)36 (16,29), (b) the nature and role of foci of enzyme-altered hepatocytes, and (c) the source and significance of Differences in methodological approaches preclude an exact comparison of the degree of cell proliferation induced by the CDAA diet in female rats (Fig. 5), and the degrees induced by the CD diet in males (16), or by a severe lipotrope-deficient diet in females (29).…”

In situ detection, by spin trapping, of hydroxyl radical markers produced from ionizing radiation in the tumor of a living mouse.

“…The production of 8-hydroxyguanine in tissue extracts or its monitoring in the urine of living animals is a nonspecific marker of oxidative stress since the presence of other mutagens not directly associated with hydroxyl radical production (7)(8)(9) may give the same result. The same holds for thiobarbituric acidreacting substances (10). For the better part of a decade, we have refined techniques to allow the detection of free radicals in living animals (11)(12)(13), and now we report our initial in vivo in situ experiments detecting free radicals we believe are derived from hydroxyl radicals produced in an irradiated tumor of a living mouse.…”

Effects of Isoliquirithigenin on the Development of Preneoplastic Liver Lesions Caused by a Choline-Deficient, L-Amino Acid-Defined Diet and on the Urinary Bladder Carcinogenesis by N-Butyl-N-(4-hydroxybutyl)nitrosamine in Rats

“…In fact, the LOX-inhibitory activity of ISO has been assumed to involve in its inhibition of platelet aggregation and mouse skin tumor promotion by either TPA or a non-TPA type promoter 8,20 . Endogenous production of reactive oxygen species and upregulation of COX-2 have been postulated to be involved in the hepatocarcinogenesis caused by a CDAA diet though involvement of LOX being unclear 15,21,22 . Thus, antioxidants such as CV-3611 (2-O-octadecylascorbic acid) (at doses above 100 ppm in the diet), ascorbic acid, α-tocopherol, trolox (1000 ppm for others), a COX-2 inhibitor nimesulide (above 200 ppm), and a LOX inhibitor nordihydroguaiaretic acid (NDGA) (above 1000 ppm), can inhibit the development of GST-P-positive foci 15,21,22 .…”

“…Endogenous production of reactive oxygen species and upregulation of COX-2 have been postulated to be involved in the hepatocarcinogenesis caused by a CDAA diet though involvement of LOX being unclear 15,21,22 . Thus, antioxidants such as CV-3611 (2-O-octadecylascorbic acid) (at doses above 100 ppm in the diet), ascorbic acid, α-tocopherol, trolox (1000 ppm for others), a COX-2 inhibitor nimesulide (above 200 ppm), and a LOX inhibitor nordihydroguaiaretic acid (NDGA) (above 1000 ppm), can inhibit the development of GST-P-positive foci 15,21,22 . Taking into account that relatively high doses of either antioxidants or LOX inhibitor appear to be required for the inhibition, the possibility cannot be excluded that higher doses of ISO might have prevented the development of preneoplastic liver lesions.…”