Devanesan P, Ariese F, Jankowiak R, Small G J, Rogan E G, Cavalieri E L
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Chem Res Toxicol. 1999 Sep;12(9):789-95. doi: 10.1021/tx980202x.
Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogenic polycyclic aromatic hydrocarbon that has been identified in the environment. Earlier studies in our laboratory indicated that more than 80% of the DB[a,l]P-DNA adducts formed in vitro were depurinating adducts and that most of the stable adducts were formed from diol epoxide intermediates. To complete the profile of both stable and depurinating adducts of DB[a,l]P, we have synthesized standard adducts by reacting 3'-dAMP or 3'-dGMP with either (+/-)-anti- or (+/-)-syn-dibenzo[a,l]pyrene 11,12-dihydrodiol 13, 14-epoxide (DB[a,l]PDE). The adducts were separated by HPLC with an ion-pair column and were identified by fluorescence line-narrowing spectroscopy (FLNS). A total of six pairs of stereoisomers along with another stable DB[a,l]PDE-DNA adduct were successfully isolated and identified. Pairs of (+/-)-trans and (+/-)-cis isomers were expected to be formed from the reaction of anti-DB[a,l]PDE with either dAMP or dGMP. While we were able to identify two pairs of stereoisomeric (+/-)-syn-DB[a,l]PDE-dAMP (cis and trans) and two pairs of stereoisomeric (+/-)-anti-DB[a,l]PDE-dAMP (cis and trans) adducts, identification of all the stereoisomers of dGMP adducts proved to be impossible. A pair of (+/-)-syn-trans-DB[a,l]PDE-dGMP adducts, a pair of (+/-)-anti-cis-DB[a,l]PDE-dGMP adducts, and one syn-cis-DB[a,l]PDE-dGMP adduct were conclusively identified by FLNS. These standard adducts will be used to identify the stable DNA adducts formed by DB[a,l]P and DB[a,l]PDE in vitro and in vivo.
二苯并[a,l]芘（DB[a,l]P）是在环境中已被鉴定出的最具致癌性的多环芳烃。我们实验室早期的研究表明，体外形成的DB[a,l]P-DNA加合物中超过80%是脱嘌呤加合物，并且大多数稳定加合物是由二醇环氧化物中间体形成的。为了完善DB[a,l]P的稳定和脱嘌呤加合物的全貌，我们通过使3'-dAMP或3'-dGMP与(+/-)-反式或(+/-)-顺式二苯并[a,l]芘11,12-二氢二醇13,14-环氧化物（DB[a,l]PDE）反应合成了标准加合物。这些加合物通过离子对柱的高效液相色谱法进行分离，并通过荧光线窄化光谱法（FLNS）进行鉴定。总共成功分离并鉴定出六对立体异构体以及另一种稳定的DB[a,l]PDE-DNA加合物。预期反式DB[a,l]PDE与dAMP或dGMP反应会形成(+/-)-反式和顺式异构体对。虽然我们能够鉴定出两对立体异构的(+/-)-顺式-DB[a,l]PDE-dAMP（顺式和反式）和两对立体异构的(+/-)-反式-DB[a,l]PDE-dAMP（顺式和反式）加合物，但事实证明不可能鉴定出dGMP加合物的所有立体异构体。通过FLNS最终鉴定出一对(+/-)-顺式-反式-DB[a,l]PDE-dGMP加合物、一对(+/-)-反式-顺式-DB[a,l]PDE-dGMP加合物以及一种顺式-顺式-DB[a,l]PDE-dGMP加合物。这些标准加合物将用于鉴定DB[a,l]P和DB[a,l]PDE在体外和体内形成的稳定DNA加合物。
