title: Neonicotinoid formaldehyde generators: possible mechanism of mouse-specific hepatotoxicity/hepatocarcinogenicity of thiamethoxam.
abstract: Thiamethoxam (TMX), an important insecticide, is hepatotoxic and hepatocarcinogenic in mice but not rats. Studies of Syngenta Central Toxicology Laboratory on species specificity in metabolism established that TMX is a much better substrate for mouse liver microsomal CYPs than the corresponding rat or human enzymes in forming desmethyl-TMX (dm-TMX), which is also hepatotoxic, and clothianidin (CLO), which is not hepatotoxic or hepatocarcinogenic. They proposed that TMX hepatotoxicity/hepatocarcinogencity is due to dm-TMX and a further metabolite desmethyl-CLO (dm-CLO) (structurally analogous to a standard inducible nitric oxide synthase inhibitor) acting synergistically. The present study considers formation of formaldehyde (HCHO) and N-methylol intermediates as an alternative mechanism of TMX hepatotoxicity/hepatocarcinogenicity. Comparison of neonicotinoid metabolism by mouse, rat and human microsomes with NADPH showed two important points. First, TMX and dm-TMX yield more HCHO than any other commercial neonicotinoid. Second, mouse microsomes give much higher conversion than rat or human microsomes. These observations provide an alternative hypothesis of HCHO and N-methylol intermediates from CYP-mediated oxidative oxadiazinane ring cleavage as the bioactivated hepatotoxicants. However, the proposed mono-N-methylol CYP metabolites are not observed, possibly further reacting in situ.
authors.affiliation: Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720-3112, United States.
authors.forename: Tami L
authors.initials: TL
authors.lastname: Swenson
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D005557:Formaldehyde / Q000493:pharmacokinetics*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D000073943:Neonicotinoids; D009574:Nitro Compounds / Q000493:pharmacokinetics* / Q000633:toxicity*; D010078:Oxazines / Q000493:pharmacokinetics* / Q000633:toxicity*; D010575:Pesticides / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D013045:Species Specificity; D000077922:Thiamethoxam; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D000073943:Neonicotinoids; D009574:Nitro Compounds; D010078:Oxazines; D010575:Pesticides; D013844:Thiazoles; D005557:Formaldehyde; D000077922:Thiamethoxam; D051544:Cytochrome P-450 CYP3A