title: Computational toxicology and the generation of mechanistic hypotheses: gamma-butyrolactone.
abstract: In this study, we use SAR approaches in an attempt to elucidate the action of gamma-butyrolactone (GBL), an illicit drug and a dietary supplement, that can cause coma and deaths in humans while exhibiting low systemic toxicity towards rodents. The lack of systemic toxicity of GBL and of its metabolite(s) was also predicted by validated SAR models. In fact using diverse SAR models, the only significant SAR prediction was that GBL had the potential for inhibiting human cytochrome P4502D6 (CYP2D6). However, inhibition of that isozyme is not necessarily associated with toxicity. It is suggested that GBL users also abuse other substances. When GBL inhibits CYP2D6 this may prevent the CYP2D6-mediated detoxification of other toxicants simultaneously consumed by the GBL user.
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Rosenkranz
mesh_terms: D015107:4-Butyrolactone / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000494:pharmacology*; D005544:Forecasting; D006801:Humans; D007527:Isoenzymes; D008956:Models, Chemical; D012377:Rodentia; D012475:Salmonella; D012997:Solvents / Q000493:pharmacokinetics* / Q000633:toxicity*; D013329:Structure-Activity Relationship; D019966:Substance-Related Disorders; D018675:Toxicity Tests
chemical_list: D007527:Isoenzymes; D012997:Solvents; D019389:Cytochrome P-450 CYP2D6; D015107:4-Butyrolactone