Structural basis of antimutagenicity of chemicals towards 4-nitroquinoline 1-oxide in Salmonella typhimurium.
Eighty-eight organic compounds representing a variety of chemical classes, a proportion of which possess antimutagenic and/or anticarcinogenic properties, were compared for their ability to inhibit the direct-acting mutagenicity of 4-nitroquinoline 1-oxide (4NQO) in strain TA100 of Salmonella typhimurium. Twelve compounds were found to decrease 4NQO-induced mutagenicity by at least 50%, with an antimutagenic potency varying over a 1225-fold range, corresponding to a 4-4900 molar excess of inhibitor over that of 4NQO. The resulting antimutagenicity data base was subjected to structural analysis by the computer automated structure evaluation (CASE) methodology, which identified one structural determinant (biophore) and four biophobes. The biophore contained the sulfhydryl group, present in three thiols and five aminothiols, all of which inhibited 4NQO mutagenicity. Conversely, the corresponding disulphides or thioethers as well as dithiocarbamates, isothiocyanates and other sulfur-containing compounds were devoid of antimutagenicity towards 4NQO. A distinctive dichotomy in the ability to inhibit 4NQO mutagenicity was observed with pairs of structurally and metabolically related compounds, such as the polyamines spermidine (antimutagenic) versus spermine and the tetrapyrroles bilirubin (antimutagenic) versus biliverdine. Curcumin and myricetin were the only inhibitors of 4NQO-induced mutagenicity out of a group of 12 phenols and three bioflavonoids, respectively. One biophobe was an oxidized sulfhydryl moiety, while the other three were derived from benzene or its derivatives. Some of these phenyl compounds are known antioxidants. Thus, nucleophilicity rather than antioxidant properties appears to play a role in antimutagenicity to 4NQO.(ABSTRACT TRUNCATED AT 250 WORDS)
De Flora
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S
Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.
Rosenkranz
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HS
Klopman
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D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D016587:Antimutagenic Agents / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D015394:Molecular Structure; D009152:Mutagenicity Tests; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
D016587:Antimutagenic Agents; D015112:4-Nitroquinoline-1-oxide