Pharmaco/toxicogenetics: mechanisms of chemical carcinogenesis; in vitro
toxicology
Dr. McQueen’s research program investigates the role of genetic
variation in susceptibility to toxicity. N-acetyltransferases
(NAT) catalyze the acetylation of the extra-cyclic amino group
of aromatic amines and hydrazines. Polymorphisms in the NAT1 and
NAT2 genes have been associated with risk of aromatic amine toxicity
including carcinogenesis. Dr. McQueen is using animal and in vitro
models to study how N-acetylation of aromatic amines and hydrazines
affects both the genotoxicity and cytotoxicity of xenobiotics.
Elucidation of the contribution of NAT to species variation is
of particular interest.
In addition to determining the role of NAT in toxicity to adults,
studies are underway to examine the relationship between NAT and
aromatic amine-induced developmental toxicity. Dr. McQueen has
shown in mice that NAT 1 and NAT 2 are expressed from mid-gestation
to birth and that embryonic tissue is capable of acetylating 4-aminobiphenyl,
a carcinogen found in tobacco smoke. Consequently, fetal as well
as maternal acetylation will contribute to 4-aminobiphenyl toxicity.
A second research interest is in vitro toxicology. Cell and bacterial
systems provide excellent models to investigate genotoxicity,
the ability of chemicals to interact with DNA. Since many carcinogens
are genotoxic, these models are useful in identifying potential
carcinogens. Monolayer cultures of hepatocytes are being utilized
to evaluate cellular and DNA damage.
Stevens, G.J., Burkey, J.L., and McQueen, C.A.: In vitro biotransformation
and toxicity of the heterocyclic amine batracylin.
Cell Biology and Toxicology, 16:31-39, 2000.
Burkey, J.L., Sauer, J.M., McQueen, C.A., and Siped, I.G.:
Cytotoxicity and genotoxicity of methyleugenol and related congeners:
A mechanism of activation of methyleugenol. Mutation
Res. 453:25-33, 2000.
Stevens, G.J., Payton, M., Sim, E., and McQueen, C.A.: N-acetylation
of the heterocyclic amine batracylin by human liver. Drug Metab.
Dispos. 27:966-971, 1999.
Dang, L.N. and McQueen, C.A.: Mutagenicity of 4-aminobiphenyl
and 4-acetylaminobiphenyl in Salmonella typhimurium strains expressing
different levels of N-acetyltransferase. Tox. Appl. Pharmacol.
159:77-82, 1999.
Mitchell, M.K, Futscher, B.W., and McQueen, C.A.: Developmental
expression of N-acetyltransferases in C57Bl/6 mice. Drug Metab.
Disp., 27:261-264, 1999.
