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It is well documented that cytochrome P450 enzymes pray a central role in metabolic resistance to natural plant toxins and synthetic pesticides. Using insecticide-susceptible and -resistant strains of Drosophila melanogaster and monophagous Sonoran Desert drosophilids, the current study looked for a correlation between resistance to toxic cactus alkaloids and resistance to pesticides (DDT and propoxur) or a toxic, noncactus alkaloid (nicotine). Resistance to cactus alkaloids in cactophilic Drosophila was not associated with resistance to DDT or propoxur. Conversely, a DDT-resistant strain of D. melanogaster (Hikone R) was no more tolerant of cactus alkaloids than a susceptible strain (Canton S). Cactus alkaloid-metabolizing Drosophila were, however, less susceptible to nicotine than a noncactophilic species (D. melanogaster strain Canton S). These data suggest that resistance to cactus alkaloids in monophagous desert Drosophila involves the activity of cytochrome P450 isoforms with substrate specificities sufficiently narrow to preclude detectable in vivo activity on compounds other than those that are chemically similar. These results are in contrast to what has generally been reported for more highly polyphagous insect species. (C) 1996 Academic Press