BACTERIAL AND MAMMALIAN CELL MUTAGENICITY OF FOUR OPTICALLY ACTIVE BAY-REGION 10,11-DIOL-8,9-EPOXIDES OF THE NITROGEN HETEROCYCLE DIBENZ[A,H]ACRIDINE (DB[A,H]ACR)
Battista, S; Kumar, S; Kole, PL; Sikka, HC; Wong, CQ; Conney, AH; Balani, SK; Jerina, DM; Wood, AW; Chang, RL
THE MUTAGENIC ACTIVITIES OF THE ENANTIOMERS OF THE DIASTEREOMERIC PAIR OF BAY-REGION 10,11-DIOL-8,9-EPOXIDES OF DB[A,H]ACR WERE EVALUATED IN HISTIDINE-DEPENDENT STRAINS OF S. TYPHIMURIUM AND IN CULTURED CHINESE HAMSTER V79 CELLS. IN STRAINS TA98 AND TA100 OF S. TYPHIMURIUM, THE (-)-[8S,9R,10R,11S] DIOL-EPOXIDE WAS THE MOST MUTAGENIC COMPOUND, INDUCING 1200 AND 6900 HIS+ REVERTANTS/NMOL, RESPECTIVELY. THE MUTAGENIC ACTIVITY OF EACH OF THE REMAINING 3 ISOMERS RELATIVE TO THE [S,R,R,S] ISOMER WAS ESSENTIALLY INDEPENDENT OF THE BACTERIAL STRAIN USED AND VARIED FROM 14 TO 72%. HOWEVER, IN CHINESE HAMSTER V79 CELLS, THE (+)-[8R,9S,10S,11R] DIOL-EPOXIDE WAS THE MOST MUTAGENIC COMPOUND (68 8-AZAGUANINE RESISTANT VARIANTS/NMOL/10(5) CELLS), INDUCING FROM 2 TO 11 TIMES AS MANY MUTATIONS AS THE OTHER 3 ISOMERS. THESE RESULTS ARE ANALOGOUS TO PREVIOUS STUDIES WITH THE BAY-REGION DIOL EPOXIDES OF OTHER POLYCYCLIC HYDROCARBONS IN THAT THE ISOMER WITH [R,S,S,R] ABSOLUTE STEREOCHEMISTRY HAS HAD VARIABLE ACTIVITY IN THE BACTERIAL ASSAYS, BUT HAS GENERALLY BEEN THE MOST ACTIVE IN THE MAMMALIAN CELLS. FURTHERMORE, THIS ISOMER HAS ALMOST ALWAYS BEEN UNIQUELY TUMORIGENIC IN THE MOUSE.