Chronic, topical exposure to benzo[a]pyrene induces relatively high steady-state levels of DNA adducts in target tissues and alters kinetics of adduct loss.

Abstract

Carcinogen-DNA adduct measurements may become useful biomarkers of effective dose and/or early effect. However, validation of this biomarker is required at several levels to ensure that human exposure and response are accurately reflected. Important Adduct levels increased with increasing dose, but the slope of the dose-response was different in each organ. At low doses, accumulation was linear in skin and lung, but at high doses the adduct levels in the lung increased dramatically at the same time when the levels in the skin reached apparent steady state. In the liver adduct, levels were lower than in target tissues and apparent steady-state adduct levels were reached rapidly, the maxima being independent of dose, suggesting that activating metabolism was saturated in this organ. Removal of adducts from skin, the target organ, was more rapid following single treatment than with chronic exposure. This finding is consistent with earlier data, indicating that some areas of the genome are more resistant to repair. Thus, repeated exposure and repair cycles would be more likely to cause an increase in the proportion ofcarcinogen-DNA adducts in repair-resistant areas of the genome. These findings indicate that single-dose experiments may underestimate the potential for carcinogenicity for compounds that follow this pattern.

The tumor promoter TPA enhances benzo[a]pyrene and benzo[a]pyrene diolepoxide mutagenesis in Big Blue� mouse skin

“…4) or DNA adducts, [data not shown; Albert et al, 1996;Talaska et al, 1996] but did increase mitotic index. ND ϭ mutant frequency was not determined; *, the mean Ϯ SD for the background mutant frequency for liver is 4.2 ϫ 10 Ϫ5 Ϯ 1.0; dot ϭ P Յ 0.05, line 5 to line 2; for lines 2 through 5, the number of plaques counted was 155,700, 228,700, 173,250, and 162,810, respectively.…”

Benzo[a]pyrene-Induced Toxicity: Paradoxical Protection in Cyp1a1(−/−) Knockout Mice Having Increased Hepatic BaP–DNA Adduct Levels

“…BaP-DNA adducts were determined by 32 P-postlabeling as described (15). In brief, DNA from liver was hydrolyzed to 3Ј-phosphodeoxynucleosides and then treated with nuclease P1, which preferentially dephosphorylates nucleotides that do not have adducts.…”

Vitamin D Receptor Activation Enhances Benzo[a]pyrene Metabolism via CYP1A1 Expression in Macrophages

“…BaP-induced DNA adducts were determined by a 32 P-postlabeling method (Talaska et al, 1996;Uno et al, 2001;Endo et al, 2008). After DNA extraction from cells, hydrolysis to 3Ј-phosphodeoxynucleotides with micrococcal endonuclease and spleen phosphodiesterase, and removal of nonadducted 3Ј-phosphodeoxynuleotides with n-butanol extraction, the 3Ј-phosphodeoxynucleosides, were labeled at the 5Ј positions with […”