Assessment of the medicines lidocaine, prilocaine, and their metabolites, 2,6-dimethylaniline and 2-methylaniline, for DNA adduct formation in rat tissues.
The local anesthetics lidocaine (lido) and prilocaine (prilo) are metabolized to their constituent aromatic amines 2,6-dimethylaniline (DMA, 2,6-xylidine) and 2-methylaniline (MA, o-toluidine), respectively, which are both tumorigenic in rats. The capacity of lido and prilo to form DNA adducts was assessed in major target tissues for aromatic amines in male F344 rats in comparison to equimolar doses of DMA and MA using the (32)P-postlabeling assay. Direct reaction of putative DNA-reactive metabolites N-hydroxy-DMA and N-hydroxy-MA with isolated DNA yielded reference adducts. Rats were dosed by p.o. gavage with 0.5 mmol/kg b.wt. of each test substance or the vehicle either once or daily for 7 days. After repeat administrations of either prilo or lido, DNA adducts were detected in the liver and nasal mucosa. Urinary bladder DNA adducts were detected only in lido and DMA repeat dosed rats. Groups dosed with DMA or MA showed adducts in both single- and multiple-dose groups, except for the single-dose DMA liver and urinary bladder samples, which were below the level of detection. No DNA adducts were detected in any of the white blood cell samples under either dosing regimen. The lido- and prilo-DNA adducts detected were chromatographically indistinguishable from those formed either in DMA- or MA-dosed rats, respectively, or by chemical reaction of the corresponding N-hydroxy derivatives with DNA. Thus, lido and prilo can generate DNA adducts in rats via their aromatic amine metabolites, although at lower levels than equal molar quantities of their amine metabolites.
Duan
Jian-Dong
JD
Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.
Jeffrey
Alan M
AM
Williams
Gary M
GM
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D018736:DNA Adducts; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D011318:Prilocaine / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D014052:Toluidines / Q000494:pharmacology*
D000814:Aniline Compounds; D018736:DNA Adducts; D014052:Toluidines; D011318:Prilocaine; C007766:2,6-xylidine; D008012:Lidocaine; C023622:2-toluidine