Quantitation of benzo[a]pyrene-DNA adducts by postlabeling with 14C-acetic anhydride and accelerator mass spectrometry.

Quantitation of carcinogen-DNA adducts provides an estimate of the biologically effective dose of a chemical carcinogen reaching the target tissue. In order to improve exposure-assessment and cancer risk estimates, we are developing an ultrasensitive procedure for the detection of carcinogen-DNA adducts. The method is based upon postlabeling of carcinogen-DNA adducts by acetylation with 14C-acetic anhydride combined with quantitation of 14C by accelerator mass spectrometry (AMS). For this purpose, adducts of benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) with DNA and deoxyguanosine (dG) were synthesized. The most promutagenic adduct of BPDE, 7R,8S,9R-trihydroxy-10S-(N(2)-deoxyguanosyl)-7,8,9, 10-tetrahydrobenzo[a]pyrene (BPdG), was HPLC purified and structurally characterized. Postlabeling of the BPdG adduct with acetic anhydride yielded a major product with a greater than 60% yield. The postlabeled adduct was identified by liquid chromatography-mass spectrometry as pentakis(acetyl) BPdG (AcBPdG). Postlabeling of the BPdG adduct with 14C-acetic anhydride yielded a major product coeluting with an AcBPdG standard. Quantitation of the 14C-postlabeled adduct by AMS promises to allow detection of attomolar amounts of adducts. The method is now being optimized and validated for use in human samples.

Structure-toxicity relationships for aminoalkanols: a comparison with alkanols and alkanamines.

The relative toxicity (log IGC50(-1)) of 49 selected aliphatic amines and aminoalkanols was evaluated in the static Tetrahymena pyriformis population growth impairment assay. Excess toxicity, indicated by potency greater than predicted for non-polar narcotic alkanols, was associated with both classes of test chemicals. Moreover, the aminoalkanols were found to be more toxic than the corresponding alkanamines. A high quality 1-octanol/water partition coefficient (log K(ow)) dependent quantitative structure-activity relationship (QSAR), logIGC50(-1) = 0.78 (log K(ow)) - 1.42; r2 = 0.934, was developed for alkanamines. This QSAR represented the amine narcosis mechanism of toxic action. No quality QSAR was developed for the aminoalkanols. However, several structure-toxicity features were observed for this class of chemicals. Two-amino-1-hydroxy derivatives being more toxic than the corresponding derivatives, where the amino and hydroxy moieties were separated by methylene groups. Hydrocarbon branching next to the amino moiety resulted in decreased toxicity. Aminoalkanol alters lipid metabolism in T. pyriformis.