Synthesis, microsome-mediated metabolism, and identification of major metabolites of environmental pollutant naphtho[8,1,2-ghi]chrysene

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Abstract

Naphtho[8,1,2-ghi]chrysene, commonly known as naphtho[1,2-e]pyrene (N[1,2-e]P) is a widespread environmental pollutant, identified in coal tar extract, air borne particulate matter, marine sediment, cigarette smoke condensate, and vehicle exhaust. Herein, we determined the ability of rat liver microsomes to metabolize N[1,2-e]P and an unequivocal assignment of the metabolites by comparing them with independently synthesized standards. We developed the synthesis of both the fjord region and the K-region dihydrodiols and various phenolic derivatives for metabolite identification. The 12-OH-N[1,2-e]P, fjord region dihydrodiol 14 and diol epoxide 15 were synthesized using a Suzuki cross-coupling reaction followed by the appropriate manipulation of the functional groups. The K-region trans-4,5-dihydrodiol (18) was prepared by the treatment of N[1,2-e]P with OsO4 to give cis-dihydrodiol 16, followed by pyridinium chlorochromate oxidation to quinone 17, and finally reduction with NaBH4 to afford the dihydrodiol 18 with the desired trans stereochemistry. The 9-OH-N[1,2-e]P (30) and N[1,2-e]P trans-9,10-dihydrodiol (32) were also synthesized following a Suzuki cross-coupling approach starting from 1,2,3,6,7,8-hexahydropyrene-4-boronic acid. The metabolism of N[1,2-e]P with rat liver microsomes led to several dihydrodiol and phenolic metabolites as assessed by the HPLC trace. The 11,12-dihydrodiol and 4,5-dihydrodiol were identified as major dihydrodiol metabolites. The synthesized 9,10-dihydrodiol, on the other hand, did not match with any of the peaks in the metabolism trace. Among the phenols, only 12-OH-N[1,2-e]P was identified in the metabolism. The other phenolic derivatives synthesized, that is, the 4-/5-, 9-, 10-, and 11-hydroxy derivatives, were not detected in the metabolism trace. In summary, N[1,2-e]P trans-11,12-dihydrodiol was the major metabolite formed along with N[1,2-e]P 4,5-trans-dihydrodiol and 12-OH-N[1,2-e]P on exposure of rat liver microsomes to N[1,2-e]P. The presence of N[1,2-e]P in the environment and formation of fjord region dihydrodiol 14 as a major metabolite in in vitro metabolism studies strongly suggest the role of N[1,2-e]P as a potential health hazard.

Original languageEnglish (US)
Pages (from-to)1154-1162
Number of pages9
JournalChemical research in toxicology
Volume21
Issue number5
DOIs
StatePublished - May 1 2008

All Science Journal Classification (ASJC) codes

  • Toxicology

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