Influence of arylamine n‐acetyltransferase, sex, and age on 4‐aminobiphenyl‐induced in vivo mutant frequencies and spectra in mouse liver

Abstract

One model for cancer initiation by 4-aminobiphenyl (ABP) involves N-oxidation by cytochrome P450 CYP1A2 followed by O-conjugation by Nacetyltransferase(s) NAT1 and/or NAT2 and decomposition to a DNA-binding nitrenium ion. We recently observed that neonatal ABP exposure produced liver tumors in male but not in female mice, and that NAT deficiency reduced liver tumor incidence. However, ABP-induced liver tumor incidence did not correlate with liver levels of N-(deoxyguanosin-8-yl)-ABP adducts 24 hr after exposure. In this study, we compared in vivo ABPinduced DNA mutant frequencies and spectra between male and female wild-type and NATdeficient Muta TM Mouse using both the tumorinducing neonatal exposure protocol and a 28-day repetitive dosing adult exposure protocol. ABP produced an increase in liver DNA mutant frequencies in both neonates and adults. However, we observed no sex or strain differences in mutant frequencies in neonatally exposed mice, and higher frequencies in adult females than males. Neonatal ABP exposure of wild-type mice increased the proportion of G-T transversions in both males and females, while exposure of Nat1/2(-/-) mice produced increased G-T transversions in males and a decrease in females, even though females had higher levels of N-(deoxyguanosin-8-yl)-4-ABP adducts. There was no correlation of mutant frequencies or spectra between mice dosed as neonates or as adults. These results suggest that observed sex-and NATdependent differences in ABP-induced liver tumor incidence in mice are not due to differences in either mutation rates or mutational spectra, and that mechanisms independent of carcinogen bioactivation, covalent DNA binding and mutation may be responsible for these differences. Environ. Mol. Mutagen. 53:350-357, 2012. V V C 2012 Wiley Periodicals, Inc.

Hepatocellular carcinoma and the risk of occupational exposure

“…Although there was a dose-related increase in 4-ABP DNA (cigarettes smoked/day) and an association with mutant p53 protein expression in bladder cancers, there are currently no reports of p53 or other specific gene mutations caused by exposure to PAH or 4-ABP in HCC [242][243][244] .…”

Relative Contributions of CYP1A2 and CYP2E1 to the Bioactivation and Clearance of 4-Aminobiphenyl in Adult Mice

“…Pretreatment of wildtype mice with the CYP1A2 inducer 2, 3,7,8-tetrachlorodibenzo[p] dioxin in the same study led to a lower, rather than a higher, level of C8-dG-ABP adducts compared with untreated mice (Tsuneoka et al, 2003). Studies from our laboratory showed that adult wild-type and Nat1/2(2/2) mice had similar in vivo plasma clearances, C8-dG-ABP adducts, and mutations following exposure to ABP, whereas postnatally exposed Nat1/2(2/2) mice had significantly reduced liver tumor incidence (Sugamori et al, 2006Wang et al, 2012). These results suggest that enzymes other than CYP1A2 and NAT1/2 are involved in the N-hydroxylation and clearance of ABP, respectively.…”

Decoloración Sonoquímica Sinérgica Del Anaranjado De Metilo Utilizando Triclorometano en Dos Reactores Ultrasónicos

“…Algunos colorantes azoicos (los clasificados como ácidos, básicos y directos) son tóxicos agudos para peces, crustáceos, algas y bacterias, mientras que los colorantes azoicos reactivos poseen valores de concentraciones efectivas muy altas (CE > 100 mg/L), por lo que son considerados no tóxicos para los organismos acuáticos (Novotny et al 2006). La acción carcinogénica y/o mutagénica de los colorantes azo puede deberse a la acción del compuesto como tal, a la formación de arilaminas a través de los procesos reductivos durante las biotransformaciones (Chung et al 1992, Collier et al 1993, Rajaguru et al 1999) o a los productos obtenidos a través de la vía oxidativa del sistema citocromo P450 (Arlt 2002, Umbuzeiro et al 2005, Wang et al 2012. Por estas razones, la eliminación del agua de estos compuestos es muy importante para la seguridad del ambiente y la salud humana (Wu et al 2012).…”