Metabolically activated steviol, the aglycone of stevioside, is mutagenic.

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Abstract
Stevioside, a constituent of Stevia rebaudiana, is commonly used as a noncaloric sugar substitute in Japan. Stevioside is not mutagenic as judged by utilization of Salmonella typhimurium strain TM677, either in the presence or in the abesnce of a metabolic activating system. Similar negative results were obtained with several structurally related sweet-tasting glycosides. Steviol, the aglycone of stevioside, was highly mutagenic when evaluated in the presence of a 9000 .times. g supernatant fraction derived from the livers of Aroclor 1254-pretreated rats. Expression of mutagenic activity was dependent on both pretreatment of the rats with Aroclor 1254 and addition of NADPH; unmetabolized steviol was not active. The structurally related species, isosteviol, was not active regardless of metabolic ativation. Chemical reduction of the unsaturated bond linking the carbon-16 and -17 positions of steviol resulted in the generation of 2 isomeric products, dihydrosteviol A and B, that were not mutagenic. ent-Kaurenoic acid was inactive. Evidently, a metabolite of an integral component of stevioside is mutagenic; structural features of requisite importance for the expression of mutagenic activity include a hydroxy group at position 13 and an unsaturated bond joining the carbon atoms at positions 16 and 17. A potential metabolite of steviol, steviol-16.alpha.,17-epoxide, was synthesized chemically and was ineffective as a direct-acting mutagen. Thus, atlhough stevioside itself appears innocuous, it would seem prudent to expeditiously and unequivocally establish the human metabolic disposition of this substance.