³²P-postlabeling Analysis of 7H-Dibenzo [c,g] carbazole and Dibenz [a,j] acridine DNA Adduct in Mice

7H-Dibenzo [c,g] carbazole과 Dibenz[a,j] acridine에 의한 DNA adduct의 ³²P-postlabeling 분석

N-Heterocyclic aromatics (NHA) are widely occurring environmental pollutants formed during the pyrolysis of nitrogen-containing organic chemicals. NAH are found in significant amounts in tobacco condensates, synthetic fuels, polluted river sediment, and effluents from the heating of coal. Following topical application 7H-dibenzo[c, g]carbazole (DBC) induces cancer in liver as well as skin, indicating that dermal exposure can lead to systemic effect. DBC and dibenz[a,j]acridine (DBA) are examples of NHA. The potency of many carcinogenic compounds is related, at least in part, to the efficiency of their biological activation. We undertook studies to determine which initial metabolites lead to the formation of high levels of carcinogen-DNA adducts in vivo. DBC and DBA's, DBA, trans-DBA-1,2-dihydrodiol (DBA-1,2-DHD), trans-DBA-3,4-dihydrodiol (DBA-3,4-DHD), and trans-DBA-5,6-dihydrodiol (DBA-5,6-DHD), were applied to the skin of mice. There were six adducts that were related to DBC application. These addusts were seen in the target organ, liver at high levels, but at very low levels in non-target organs, skin, lung and kidney. In skin, DBA produced two distinct adducts. The same two adducts were seen when DBA-3,4-DHD was applied. In addition the total adduct level elicited by DBA-3,4-DHD higher than that of parent compound. Two adducts were seen when DBA-5,6-DHD was applied, but these were very different from adducts seen with DBA. These results suggested that activation of DBA to DNA-binding compounds in skin includes initial formation of DBA-3,4-DHD.

7H-dibenzo[c,g]carbazole(DBC)과 dibenz[a, j]acridine(DBA) 및 이의 대사물 trans-DBA-1,2-dihydrodiol(DBA-1,2-DHD), trans-DBA-3,4-dihydrodiol(DBA-3,4-DHD), trans-DBA-5,6-dihydrodiol(DBA-5,6-DHD)]에 의한 DNA adduct형성을 알기 위해 Hsd:ISR 생쥐 피부에 이를 투여하고 용매 추출법으로 DNA를 분리하고 $^{32}P$-postlabeling법으로 DNA adduct를 분석하였다. DBC를 피부에 투여하여 DNA adduct가 국소작용 부위인 피부와 내장기관인 간, 폐 및 신장에 형성되어 DBC는 국소 및 전신 발암작용이 있음을 알 수 있었다. 또한 DNA adduct활성도가 간에서는 높고 피부, 폐, 신장에서는 상대적으로 낮아 DBC에 의한 발암의 주 표적 장기는 간임을 추측할 수 있었다. DBA, DBA-3,4-DHD 및 DBA-5,6-DHD 투여에 의해 두개의 adduct가 피부에서 관찰되었다. 대사 물질인 DBA-5,6-DHD에 의해 2개의 adduct가 형성되었으나 그 양상이 DBA 및 DBA-3,4-DHD와는 달랐으며 DBA-1,2-DHD에 의해서는 DNA adduct 형성이 관찰되지 않았다. 이상의 결과로 DBA는 국소발암작용이 있으며 활성 대사물인 DBA-3,4-DHD가 최종 발암원(ultimate carcinogen)이고 DBA-1,2-DHD는 무독화 대사물질로 추측된다.