James Flesher,
Ph.D.
Professor
Pharmacology
Phone:
(859) 323-5125
Fax:
(859) 323-1981
e-mail:
jwflesh@uky.edu
|
Research Interests The unified
hypothesis, for the carcinogenic properties of polycyclic aromatic hydrocarbons (PAH)
predicts that 7-hydroxymethyl sulfate ester (SMBA) plays a major role in the metabolic
activation, DNA binding, and complete carcinogenicity of 7,12-dimethylbenz[a]anthracene
(DMBA). However, alternative hypotheses predict that other pathways may play a role in
DMBA carcinogenesis. It is a matter of considerable interest to identify clearly the
ultimate electrophilic and carcinogenic forms of DMBA. To test the validity and generality
of our hypothesis, we plan to carry out: 1) the preparation and characterization of
selected DMBA derivatives, 2) the metabolism of DMBA and selected derivatives/metabolites
in rat-liver homogenates, in vitro, and in liver and mammary gland, in vivo. The products
of metabolism will be identified and compared with a number of reference compounds by HPLC
and GC/MS, 3) the identification of the most carcinogenic forms of DMBA and of the model
metabolite 7-formyl-12-methylbenz[a]anthracene (7-FMBA) in a complete carcinogenesis
model, 4) the formation and identification of DMBA and 7-FMBA related DNA adducts, in
vitro and in vivo, using the 32P-postlabeling assay together with LC/MS/MS. Sulfation of
the 7-hydroxymethyl derivative and other hydroxyalkyl derivatives of PAH, by
3'-phosphoadenosine-5'-phosphosulfate-dependent sulfotransferase activity, can
metabolically activate primary and secondary benzylic alcohol derivatives to ultimate
electrophilic mutagens and carcinogens. Since the aralkylating agents formed may be the
most carcinogenic derivatives of PAH yet identified, electrophilic hydroxyalkyl sulfate
ester formation appears to be a major pathway of the metabolic activation of proximate
carcinogens to DNA damaging ultimate carcinogens. Work done by our group and by others has
resulted in enough evidence to convince many researchers that electrophilic hydroxyalkyl
sulfate esters, and closely related aralkylating agents, play a major role in causing DNA
damage, mutagenesis, and carcinogenesis. Identification of the ultimate electrophilic and
carcinogenic forms of DMBA and 7-FMBA may eventually lead to methods for the prevention of
some of the human cancer that is currently considered to be caused by this class of
chemical carcinogens.
Research Publications/Presentations
J.W. Flesher, J. Horn, and A.F.
Lehner (1996) Molecular modeling of carcinogenic potential in polycyclic hydrocarbons. J.
Mol. Struct., 362, 29-49.
A.F. Lehner, J. Horn, and J.W.
Flesher (1996) Benzylic carbonium ions as ultimate carcinogens of polynuclear aromatic
hydrocarbons. J. Mol. Struct., 366, 203-217.
J. Horn, J.W. Flesher, and A.F.
Lehner (1996) 1-Sulfooxymethylpyrene is an electrophilic mutagen and ultimate carcinogen
of 1-methyl- and 1-hydroxymethylpyrene. Biochem. Biophys. Res. Comm., 228, 105-109.
J.W. Flesher, J. Horn, and A.F.
Lehner (1997) 7-Sulfooxymethylbenz[a]anthracene is an ultimate electrophilic and
carcinogenic form of 7-hydroxymethylbenz[a]anthracene. c
J.W. Flesher, J. Horn, and A.F.
Lehner (1997) 7-Sulfooxymethyl-12-methylbenz[a]anthracene is an exceptionally reactive
electrophilic mutagen and ultimate carcinogen. Biochem. Biophys. Res. Comm., 231,
144-148.
J.W. Flesher,
J.Horn, and A.F. Lehner (1998) Carcinogenicity of
1-Hydroxy-3-methylcholanthrene and Its Electrophilic Sulfate Ester
1-Sulfooxy-3-methylcholanthrene in Sprague-Dawley Rats. Biochem. Biophys. Res. Comm.,
243, 30-35.
J.W.
Flesher, J.Horn, and A.F. Lehner (1998) 9-Sulfooxymethylanthracene Is an
Ultimate Electrophilic and Carcinogenic Form of 9-Hydroxymethylanthracene.
Biochem. Biophys. Res. Comm., 251, 239-243.
J.W. Flesher,
J.Horn, and A.F. Lehner (1999) Role of Hydroxymethyl Sulfate Esters in
Aromatic Hydrocarbon carcinogenesis. Polycyclic Aromatic Compounds, 16,
1-11.
|
