Comparative metabolism in vitro of a novel carcinogenic polycyclic aromatic hydrocarbon, 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene, and its two regioisomeric B-ring fluoro analogues.
A novel biotransformation pathway likely exists for carcinogenic 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene (THDMBA), since this A-ring-reduced polycyclic aromatic hydrocarbon does not have an aromatic bay-region. The comparative metabolism of THDMBA, a non-carcinogenic 5F analogue, and a more carcinogenic 6F-THDMBA species was examined to determine potential DNA-bonding metabolites. Rat liver microsomes from phenobarbital-treated animals were incubated in the presence of THDMBA (or fluoro-THDMBA), NADPH, and O2. Metabolic products and the parent compound were extracted into organic solvent and analyzed/purified using reversed-phase high-performance liquid chromatography. Structure identification of metabolites using proton nuclear magnetic resonance, mass spectroscopy, and ultraviolet/visible spectroscopy indicated that hydroxylations at benzylic C1 and at the C7- and C12-CH3 functions are major oxidation products of THDMBA. Major metabolites for the noncarcinogenic 5F-THDMBA are the C4-hydroxy, C7-hydroxymethyl, and C12-hydroxymethyl derivatives. However, the potent carcinogen 6F-THDMBA only yielded major hydroxylation products at C1 and C12-CH3. These results together with a consideration of the electronic and steric effects of fluorine and the biological activities of these polycyclic aromatic hydrocarbons suggest that hydroxylation at the hindered benzylic C1 position or the C12-CH3 group of THDMBA is important for the biotransformation of such polycyclic aromatic hydrocarbons to DNA-bonding species.
Rinderle
S J
SJ
College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, Ohio State University, Columbus 43210.
Black
S D
SD
Sharma
P K
PK
Witiak
D T
DT
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D002250:Carbon Radioisotopes; D002273:Carcinogens; C074802:5-fluoro-(1,2,3,4-tetrahydro-7,12-dimethylbenz(a)anthracene); C074803:6-fluoro-(1,2,3,4-tetrahydro-7,12-dimethylbenz(a)anthracene); D015127:9,10-Dimethyl-1,2-benzanthracene; D010634:Phenobarbital