title: Comparative metabolism of the aza polynuclear aromatic hydrocarbon dibenz[a,h]acridine by recombinant human and rat cytochrome P450s.
abstract: To assess the role of human and rat cytochrome P450s in the metabolism of aza-polynuclear aromatic hydrocarbons (aza-PAHs) and to examine the influence of heterocyclic nitrogen on the metabolism of these chemicals, we have investigated the biotransformation of dibenz[a,h]acridine (DB[a,h]ACR), an aza-PAH with two nonidentical bay regions, by recombinant human cytochromes P450 1A1, 1B1, and 3A4 and rat P450 1A1. Among the three P450s, 1A1 was the most effective in metabolizing DB[a,h]ACR followed by 1B1 and 3A4. The major DB[a,h]ACR metabolites produced by human P450 1A1 and 1B1 were the dihydrodiols with a bay region double bond, namely, DB[a,h]ACR-3,4-diol and DB[a,h]ACR-10,11-diol (putative proximate carcinogen). P450 1A1 produced a higher proportion of DB[a,h]ACR-10,11-diol (derived from the benzo ring adjacent to the nitrogen) (44.7%) than of DB[a,h]ACR-3,4-diol (derived from benzo ring away from the nitrogen) (23.8%). In contrast, 1B1 produced a much greater proportion of 3,4-diol (54.7%) than of 10,11-diol (6.4%). These data indicate that (i) human P450 1A1 and 1B1 differ dramatically with respect to the regiospecific metabolism of DB[a,h]ACR, (ii) human P450 1A1 is substantially more active than human P450 1B1 in the metabolic activation of the aza-PAH to its 10,11-diol, and (iii) the presence of nitrogen influences the relative extent to which the two benzo ring diols with a bay region double bond are formed by human P450s 1A1 and 1B1. In contrast to human P450s 1A1 and 1B1, rat P450 1A1 showed no regioselectivity in the metabolism of DB[a,h]ACR producing nearly equal proportions of 10,11-diol and 3,4-diol. Despite significant differences in their regioselectivity, human P450 1A1 and 1B1 and rat P450 1A1 showed similar stereoselectivity in the metabolism of DB[a,h]ACR to its diols having a bay region double bond, producing primarily the R,R enantiomers (>94%). The data of these studies indicate that human and rat P450 1A1 differ in their regioselectivity in the metabolism of DB[a,h]ACR to its two benzo ring diols with a bay region double bond and consequently in their ability to metabolically activate the parent aza-PAH. However, human and rat P450 1A1 do not differ with respect to their stereoselectivity in the metabolism of DB[a,h]ACR to the diols.
authors.affiliation: Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York College at Buffalo, 1300 Elmwood Avenue, Buffalo, New York 14222, USA.
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Yuan
authors.forename: Subodh
authors.initials: S
authors.lastname: Kumar
authors.forename: Harish C
authors.initials: HC
authors.lastname: Sikka
mesh_terms: D000166:Acridines / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000166:Acridines; D001372:Aza Compounds; D002250:Carbon Radioisotopes; D002273:Carcinogens; D004852:Epoxy Compounds; D011084:Polycyclic Aromatic Hydrocarbons; D011994:Recombinant Proteins; C022289:dibenzacridine; D003577:Cytochrome P-450 Enzyme System; D009584:Nitrogen