Nucleophilic index value: implication in the protection by indole-3-carbinol from N-nitrosodimethylamine cyto and genotoxicity in mouse liver.
A novel assay system was developed in order to quantitate the nucleophilicity of pure chemicals or tissue extracts. This Nucleophilic Index Value (NIV) assay was based on the ability of putative nucleophiles to inhibit the methylation of cysteine by limiting concentrations of the electrophilic source, N-methyl-N-nitrosourea (MNU). Efficacy of model and cellular nucleophiles was quantitated as nmol cysteine protected by the nucleophile from methylation by MNU/h/mM compound. The NIVs of the pure compounds ascorbate, glutathione, 4-(4-nitrobenzyl)-pyridine (NBP) and indole-3-carbinol (I-3-C) were 2400, 1600, 3 and 0, respectively. When mice were treated with I-3-C by gavage at dosages of 0, 25, 50, 75 or 100 mg/kg body wt, the NIV for ethyl acetate extracts of the livers 1 h after treatment were 0, 33, 47, 52 and 92 nmol cysteine preserved/h/g tissue, respectively. The I-3-C enhancement of NIV was not attributable to ascorbate or glutathione, neither of which were present in the ethyl extracts of liver. When mice were treated with 10 mg N-nitrosodimethylamine (NDMA)/kg body wt 1 h after the varying dosages of I-3-C, the 24 h post-NDMA plasma alanine transaminase (ALT) values were decreased by I-3-C pretreatment in a dose-dependent fashion. Plasma ALT values were used in this study as an indicator of hepatotoxicity. The coefficient of determination, r2, computed from the linear least squares correlation coefficient between NIV and ALT values, was 0.80 (0-100 mg I-3-C/kg) and 0.97 (0-75 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Shertzer
H G
HG
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056.
Tabor
M W
MW
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013723:Teratogens
D007211:Indoles; D013723:Teratogens; D004247:DNA; C016517:indole-3-carbinol; D000410:Alanine Transaminase; D004128:Dimethylnitrosamine