Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin

Subodh Kumar, Richard L. Chang1,4,, Alexander W. Wood2,, Jian Guo Xie1,, Mou Tuan Huang1,, Xiao Xing Cui1,, Panna L. Kole, Harish C. Sikka, Suresh K. Balani3,, Allan H. Conney1, and Donald M. Jerina3,

Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York, College at Buffalo, Buffalo, NY 14222,
1 Laboratory for Cancer Research, Rutgers, The State University of New Jersey, College of Pharmacy, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020,
2 Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110 and
3 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
CD-1 female mice were initiated with a single topical application of 500 nmol dibenz[a,h]acridine (DB[a,h]Acr), its racemic trans-1,2-, 3,4-, 8,9- and 10,11-dihydrodiols, racemic DB[a,h]Acr 3,4-diol 1,2-epoxide-1 and -2 or racemic DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2, where the benzylic hydroxyl group is either cis (isomer 1) or trans (isomer 2) to the epoxide oxygen. The mice were subsequently treated twice weekly with 12-O-tetradecanoylphorbol 13-acetate for 25 weeks. High tumorigenicity was observed only for DB[a,h]Acr, its 10,11-dihydrodiol and DB[a,h]Acr 10,11-diol 8,9-epoxide-2 (3.3, 1.2 and 1.6 tumors/mouse, respectively). The tumor-initiating activity of a 50 nmol dose of DB[a,h]Acr and the optically active (+)- and (–)-enantiomers of DB[a,h]Acr 10,11-dihydrodiol and of the optically active DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2 were also studied. Only DB[a,h]Acr, (–)-DB[a,h]Acr (10R,11R)-dihydrodiol and the bay region (+)-(8R,9S,10S,11R)-diol epoxide-2 were highly active (1.6, 1.7 and 2.4 tumors/mouse, respectively). These results are consistent with previous studies which showed that the corresponding bay region RSSR diol epoxides of benzo[a]pyrene, benz[a]anthracene, chrysene and benzo[c]phenanthrene as well as the aza-polycyclic dibenz[c,h]acridine are the most tumorigenic isomers.

Abbreviations: PAH, polycyclic aromatic hydrocarbon; DB[a,h]Acr, dibenz[a,h]acridine; dihydrodiols, the trans-dihydroxydihydro derivatives in which the hydroxyl groups are at either the 1,2-, 3,4-, 8,9- or 10,11-positions; (±)-DB[a,h]Acr 3,4-diol 1,2-epoxide-1, (±)-3{alpha}, 4ß-dihydroxy-1ß, 2ß-epoxy-1,2,3,4-tetrahydrodibenz[a,h]acridine in which the benzylic hydroxyl group and the epoxide oxygen are cis; (±)-DB[a,h]Acr 3,4-diol 1,2-epoxide-2, (±)-3{alpha}, 4ß-dihydroxy-1{alpha},2{alpha}-epoxy-1,2,3,4-tetrahydrodibenz[a,h] acridine in which the benzylic hydroxyl group and the epoxide oxygen are trans; other diol epoxides are similarly designated; (–)-(8S,9R, 10S,11R)-diol epoxide-1, (–)-(10S, 11R)-dihydroxy-(8S,9R)-epoxy-8,9,10,11-tetrahydrodibenz[a,h]acridine; (+)-(8R, 9S,10R, 11S)-diol epoxide-1, (+)-10R, 11S)-dihydroxy-(8R,9S)-epoxy-8,9,10,11-tetrahydrodibenz[a,h]acridine; (–)-(8S,9R,10R,11S)-diol epoxide-2, (–)-(10R,11 S)-dihydroxy-(8S,9R)-epoxy-8,9,10,11-tetrahydrodibenz[a,h]acridine; (+)-(8R, 9S,10S,11R)-diol epoxide-2, (+)-(10S, 11R)-dihydroxy-(8R, 9S)-epoxy-8,9,10,11-tetrahydro-dibenz[a,h]acridine; PAH, polycyclic aromatic hydrocarbon. The designations {alpha} and ß denote opposite faces of the hydrocarbon in the racemic compounds.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Polycyclic aromatic hydrocarbons (PAHs) derived from incomplete combustion of organic matter are widespread environmental contaminants found in automobile exhaust, cigarette smoke, air, water, food and soil (1,2). The basic fractions of these environmental samples contain a number of nitrogen heterocycles (aza-PAHs) (25) which are reported to be carcinogenic in experimental animals (59). Of all the anthropogenic compounds the PAHs have received the most attention, while their aza analogs, aza-PAHs, have been less widely studied. Within the past 15 years the concept of metabolic activation of PAHs through the bay region diol epoxide pathway has been extended by us and others to a number of aza-PAHs such as benz[c]acridine (1012), benz[a]acridine (12), 7-methylbenz[c]acridine (13), dibenz[a,j]acridine (5,14) and dibenz[c,h]acridine (9,15,16). These studies revealed that the position of the nitrogen heteroatom in an aza-PAH can have a significant effect on the carcinogenic potencies of their known or potential dihydrodiol and bay region diol epoxide metabolites. In the present study we have extended this line of investigation and evaluated the carcinogenic activity of the dihydrodiol and diol epoxide derivatives of dibenz[a,h]acridine (DB[a,h]Acr) (Figure 1Go), a carcinogenic aza analog of dibenz[a,h]anthracene. The substitution of nitrogen for the carbon at position 7 of dibenz[a,h]anthracene eliminates the perpendicular C2 axis of symmetry and, consequently, renders the two bay regions of the resulting DB[a,h]Acr non-equivalent. Thus, the study of DB[a,h]Acr will allow us to compare the effects of the presence and absence of the nitrogen heteroatom in the bay region of a PAH on the tumorigenicity of the bay region diol epoxides.



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Fig. 1. Structures of the nitrogen heterocycle DB[a,h]Acr and 14 of its derivatives studied in this report. Lettering of the acridine bonds begins at the bond with the first fused benzo ring (top right) and proceeds clockwise around the ring system. Absolute configurations of the optically active compounds are indicated.

 
Based on qualitative resonance calculations (1720), the bay region 10,11-diol 8,9-epoxide derived from the 8,9,10,11-benzo ring of DB[a,h]Acr is expected to be more reactive and, potentially, more carcinogenic than the bay region 3,4-diol 1,2-epoxide derived from the 1,2,3,4-benzo ring. Our earlier studies of mutagenic activity in Chinese hamster V79 cell lines and in Salmonells typhimurium supported the above proposal based on the observation that the DB[a,h]Acr 10,11-diol 8,9-epoxide diastereomers (the nitrogen heteroatom forms part of the bay region) were 20–80 times more mutagenic than the DB[a,h]Acr 3,4-diol 1,2-epoxide diastereomers (nitrogen heteroatom remote from the bay region) (21). In the light of this and our earlier findings that the four possible bay region diol epoxide isomers with different absolute configurations have markedly different biological activities (9,18) we sought to evaluate the tumorigenic activities of the four possible DB[a,h]Acr 10,11-diol 8,9-epoxide isomers in order to further probe whether the stereochemical requirements for tumorigenicity observed for the PAH diol epoxides can be extended to their aza analogs. An increased understanding of the factors responsible for subtle differences in tumorigenicity between closely related bay region diol epoxide stereoisomers of PAHs and their aza analogs should shed light on the mechanisms responsible for carcinogenesis. In the present study we have evaluated the tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle DB[a,h]Acr on mouse skin. A preliminary report of these studies has appeared (22).


    Materials and methods
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 Abstract
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 Materials and methods
 Results
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 References
 
Chemicals
DB[a,h]Acr (>98% purity by HPLC) was obtained from the Midwest Research Institute (Kansas City, MO). The racemic pairs of diastereomeric DB[a,h]Acr 3,4-diol 1,2-epoxide-1 and -2 and DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2, their synthetic precursors (±)-DB[a,h]Acr 3,4-dihydrodiol and (±)-DB[a,h]Acr 10,11-dihydrodiol were obtained at >98% chemical purity by unequivocal synthesis as described earlier (23,24). Synthesis of the (+)- and (–)-enantiomers of DB[a,h]Acr 10,11-dihydrodiol and their conversion to the enantiomerically pure (+)- and (–)-isomers of the diastereomeric pairs of DB[a,h]Acr 10,11-diol 8,9-epoxides have been described (25). All four enantiomers were >98% chemically as well as enantiomerically pure. Structures of the compounds studied and their relative and/or absolute stereochemistry are illustrated in Figure 1Go. All the compounds were dissolved in spectral grade acetone (Burdick and Jackson, Muskegan, MI) and stored under an atmosphere of argon in amber vials at –80°C.

Tumor studies on mouse skin
Tumor studies on mouse skin were similar to those described earlier (10). Female CD-1 mice at 6 weeks of age were obtained from Charles River Breeding Laboratories (Kingston, NY). The mice were housed in polycarbonate boxes with corn cob bedding, were fed Purina Laboratory chow (Ralston Purina, St Louis, MO) and were given water ad libitum. After 1 week acclimation the mice were shaved on the dorsal surface with an electric clipper. Two days later 30 mice in each treatment group were given a single topical application of the appropriate compound in 200 µl of acetone. Control animals received 200 µl of acetone. The tumor promotor 12-O-tetradecanoylphorbol 13-acetate (16 nmol/200 µl of acetone) was applied topically twice weekly, beginning 9 days after application of the initiator or solvent. Animals were maintained under standard conditions (22 ± 2°C, 50 ± 10% relative humidity, 12 h light/12 h dark cycle). Development of skin tumors was recorded every 2 weeks and papillomas >2 mm in diameter were included in the cumulative total provided they persisted for 2 weeks or longer.


    Results
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Tumorigenicity of the racemic derivatives of DB[a,h]Acr on mouse skin
The results of tumor initiation studies with DB[a,h]Acr, its four (±)-dihydrodiols and its four bay region (±)-diol epoxide derivatives after 25 weeks promotion with 12-O-tetradecanoylphorbol 13-acetate are summarized in Table IGo. The parent hydrocarbon DB[a,h]Acr was found to be the most potent tumor initiator. It produced an average of 3.33 tumors/mouse and 80% of the mice had tumors at an initiating dose of 500 nmol. Of the four possible benzo ring dihydrodiols of DB[a,h]Acr only (±)-DB[a,h]Acr 10,11-dihydrodiol, the potential metabolic precursor of a bay region diol epoxide, had substantial tumor-initiating activity. However, this racemic dihydrodiol not only produced a lower tumor incidence (percentage of mice with tumors) but also caused fewer tumors than the parent hydrocarbon DB[a,h]Acr. The remaining (±)-dihydrodiols, including (±)-DB[a,h]Acr 3,4-dihydrodiol, the potential metabolic precursor of another bay region diol epoxide, exhibited 7–18 times less tumor-initiating activity compared with (±)-DB[a,h]Acr 10,11-dihydrodiol when the data were expressed as average number of tumors per mouse.


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Table I. Tumor-initiating activity of dibenz[a,h]acridine and its racemic dihydrodiols and diol epoxides on mouse skin after 25 weeks promotion
 
The racemic bay region 10,11-diol 8,9-epoxide-2 with nitrogen in the bay region had tumor-initiating activity that was similar to that of its potential metabolic precursor, (±)-DB[a,h]Acr 10,11-dihydrodiol (Table IGo). As expected, the related diol epoxide-1 isomer, in which the benzylic hydroxyl group and the oxirane ring are in cis, was only 1/8 as active as its diol epoxide-2 diastereomer. Interestingly, racemic bay region 3,4-diol 1,2-epoxide isomer-1 and -2, which lack nitrogen in the bay region, were 8–22 times less active than (±)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2, but their tumorigenic activities were comparable to that of (±)-DB[a,h]Acr 3,4-dihydrodiol, their potential metabolic precursor.

Tumorigenic activity of DB[a,h]Acr and its optically active derivatives on mouse skin
The skin tumor-initiating activities of DB[a,h]Acr, its optically pure (+)-(10R,11R)- and (–)-(10S,11S)-dihydrodiols and the four optically pure isomers of the DB[a,h]Acr 10,11-diol 8,9-epoxides are given in Table IIGo. In this second experiment each compound was tested at two dose levels (50 and 175 nmol) and the percent of mice with tumors and tumors/mouse were recorded after 10 and 20 weeks promotion with 12-O-tetradecanoylphorbol 13-acetate. Of the several compounds tested (Table IIGo) only (+)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 showed substantial tumorigenic activity after 10 weeks promotion. At both of the dose levels tested the parent compound DB[a,h]Acr produced a substantial tumor incidence only after 20 weeks promotion with 12-O-tetradecanoylphorbol 13-acetate.


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Table II. Tumor-initiating activity of DB[a,h]ACR and its derivatives on mouse skin
 
For the two optically pure isomers of DB[a,h]Acr 10,11-dihydrodiol only the (–)-(10R,11R)-dihydrodiol had tumor-initiating activity comparable to that of DB[a,h]Acr after 20 weeks promotion when the data were expressed as average number of tumors per mouse. (+)-DB[a,h]Acr 10,11-dihydrodiol did show significant tumor-initiating activity, but it was only 1/3 that of (–)-DB[a,h]Acr 10,11-dihydrodiol at the 175 nmol dose. At the lower dose (50 nmol) no significant drop in the tumor-initiating activity was noted for (–)-DB[a,h]Acr 10,11-dihydrodiol, while (+)-DB[a,h]Acr 10,11-dihydrodiol had little or no activity. All four optically active isomers of DB[a,h]Acr 10,11-diol 8,9-epoxide exhibited significant tumor-initiating activity at the higher dose (175 nmol), but only (+)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 exhibited substantial tumor-initiating activity at the lower dose. At all dose levels tested (+)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 was ~7- to 10-fold more active than the other three diol epoxide isomers (Table IIGo). Furthermore, in contrast to the other diol epoxide isomers, which showed no substantial tumor-initiating activity after 10 weeks promotion, (+)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 produced an 85% tumor incidence and an average of 2.3 tumors/mouse at the 175 nmol initiating dose.

Although racemic (±)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 was only half as active as DB[a,h]Acr (Table IGo), the optically active (+)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 enantiomer was nearly 3-fold more active than DB[a,h]Acr at the dose level tested (Table IIGo).


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The results obtained with the racemic benzo ring dihydrodiols of DB[a,h]Acr on mouse skin demonstrated marked differences in their tumorigenic activities. Large differences in the tumorigenic potencies of the racemic bay region diol epoxides of DB[a,h]Acr were also evident in this study. As expected from a number of earlier studies with analogous racemic derivatives of PAHs and a few aza-PAHs (911,26), the relative configuration of the bay region diol epoxides (diol epoxide-1 versus diol epoxide-2) of DB[a,h]Acr also plays a significant role in the expression of tumorigenic activity. Thus (±)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 and its metabolic precursor (±)-DB[a,h]Acr 10,11-dihydrodiol were the only DB[a,h]Acr derivatives which showed substantial tumorigenic activity. The analogous diol epoxides derived from the 1,2,3,4-benzo ring of DB[a,h]Acr had little or no tumorigenic activity in this assay. These data are consistent with our previous mutagenicity data with these racemic diol epoxides indicating that (±)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 has the highest mutagenic activity in both bacterial (S.typhimurium strains TA98 and TA100) and mammalian (Chinese hamster V79) cells (21). The greater biological activity observed for (±)-DB[a,h]Acr 10,11-diol 8,9-epoxide-2 but not for (±)-DB[a,h]Acr 3,4-diol 1,2-epoxide-2 is also consistent with the bay region hypothesis which predicts a direct correlation between the biological activity of the diol epoxides and the ease of carbonium ion formation from the epoxide moiety of these diol epoxides (9,1720). The ease of carbonium ion formation from the diol epoxide is facilitated by the capacity of the hydrocarbon to delocalize the positive charge of the carbonium ion throughout the Pi electron system of the aromatic nucleus of the hydrocarbon. The resonance of the C-1 carbonium ion formed by ring opening of the bay region diol epoxide places a positive charge on the nitrogen heteroatom of DB[a,h]Acr 3,4-diol 1,2-epoxide, but this is not the case for the C-8 carbonium ion of DB[a,h]Acr 10,11-diol 8,9-epoxide. Since delocalization of the positive charge on the electronegative nitrogen heteroatom is energetically destabilizing, one would expect DB[a,h]Acr 3,4-diol 1,2-epoxide to be less ractive than DB[a,h]Acr 10,11-diol 8,9-epoxide (19).

The results obtained with the (+)- and (–)-enantiomers of the 10,11-dihydrodiol and its diastereomeric bay region diol epoxides on mouse skin also demonstrated a marked difference in their tumorigenic activities. In a 20 week promotion study all four optical isomers of DB[a,h]Acr 10,11-diol 8,9-epoxide had significant tumorigenic activity at the highest dose (175 nmol) tested. However, except for DB[a,h]Acr (+)-(8R,9S,10S,11R)-diol epoxide-2, which had ~3-fold greater tumor-initiating activity on mouse skin than did DB[a,h]Acr, the other three isomers were only 1/3 as tumorigenic as DB[a,h]Acr. The high tumorigenic activity observed for DB[a,h]Acr (+)-(8R,9S,10S,11R)-diol epoxide-2 was predicted based on our mutagenicity studies with DB[a,h]Acr diol epoxide isomers in Chinese hamster V79 cells (26). Although the racemic DB[a,h]Acr 10,11-diol 8,9-epoxide-2 was only half as tumorigenic as the parent hydrocarbon, DB[a,h]Acr (+)-(8R,9S,10S,11R)-diol epoxide-2 was ~3-fold more tumorigenic than DB[a,h]Acr. An inhibitory interaction between diol epoxide enantiomers on tumorigenicity has not been previously noted; however, enantiomeric synergism is known to occur for the carcinogenicity of benzo[a]pyrene 7,8-oxide (27). At a low initiating dose (50 nmol/mouse) DB[a,h]Acr and its bay region diol epoxide DB[a,h]Acr (+)-(8R,9S,10S,11R)-diol epoxide-2 showed substantial tumorigenic activity (1.6–2.4 tumors/mouse). The remaining three diol epoxide isomers had no substantial activity at this dose (0.2–0.3 tumors/mouse). The observation that the (+)-(8R,9S,10S,11R)-diol epoxide-2 stereoisomer had the highest tumorigenic activity of the DB[a,h]Acr diol epoxides is in accord with observations for other PAHs that also indicate high tumorigenicity for bay region (R,S)-diol (S,R)-epoxides (28). However, the observation that the remaining three diol epoxide isomers had tumorigenic activity significantly lower than that of DB[a,h]Acr sharply contrasts with the results of an earlier study (15) with diol epoxides from isomeric DB[c,h]Acr, the only other aza-PAH studied extensively. For DB[c,h]Acr all four optically pure DB[c,h]Acr 3,4-diol 1,2-epoxide isomers had tumorigenicity equal to or higher than that of the parent DB[c,h]Acr. Of the many PAHs studied only benzo[c]phenanthrene, which contains a highly sterically hindered bay region (fjord region), has displayed analogous behavior (29). A complete explanation for the unusual tumorigenicity observed in DB[c,h]Acr diol epoxide isomers other than the isomer with the (1R,2S,3S,4R) absolute configuration is presently not possible. However, in view of our present finding that only the (+)-(8R,9S,10S,11R)-diol epoxide-2 isomer displayed tumorigenic activity higher than that of DB[a,h]Acr it appears that the presence of an angular benzo ring adjacent to the bay region, rather than the presence of the nitrogen heteroatom in the bay region, is responsible for the unusual tumorigenicity observed for the other three DB[c,h]Acr diol epoxide isomers.

Studies on the metabolism of DB[a,h]Acr (30) indicate that despite having an effect on tumorigenicity, the presence of a nitrogen heteroatom has essentially no effect on the formation of dihydrodiols with an adjacent bay region double bond since 3,4- and 10,11-dihydrodiols are formed in essentially equivalent amounts by rat liver microsomes. Our more recent study (31) also indicated that DB[a,h]Acr is metabolized predominantly to the more tumorigenic (+)-(8R,9S,10S,11R)-isomer of the enantiomeric DB[a,h]Acr-10,11-diol 8,9-epoxides. These results, coupled with those described in the present study, support the hypothesis that DB[a,h]Acr (+)-(8R,9S,10S,11R)-diol epoxide-2 is the ultimate carcinogenic metabolite of DB[a,h]Acr.


    Notes
 
4 To whom correspondence should be addressed Email: florek{at}rci.rutgers.edu Back


    Acknowledgments
 
We thank Ms Florence Florek for her help in the preparation of this manuscript. The studies described here were supported in part by NIH grant CA49756 and NIEHS grant ESO3346.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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  24. Kumar,S. and Agarwal,N.L. (1986) Synthesis of dihydrodiols and diol epoxides of dibenz[a,h]acridine. J. Org. Chem., 51, 2445–2449.[ISI]
  25. Kumar,S., Kole,P.L., Balani,S.K. and Jerina,D.M. (1992) Synthesis of enantiomerically pure bay-region 10,11-diol-8,9-epoxide diastereomers of the carcinogen dibenz[a,h]acridine. J. Org. Chem., 57, 2784–2787.[ISI]
  26. Chang,R.L., Battista,S., Wong,C.-Q., Kumar,S., Kole,P.L., Sikka,H.C., Balani,S.K., Jerina,D.M. and Conney,A.H. (1993) 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. Carcinogenesis, 14, 2233–2237.[Abstract]
  27. Levin,W., Buening,M.K., Wood,A.W., Chang,R.L., Kedzierski,B., Thakker,D.R., Boyd,D.R., Gadaginamath,G.S., Armstrong,R.N., Yagi,H., Karle,J.M., Slaga,T.J., Jerina,D.M. and Conney,A.H. (1980) An enantiomeric interaction in the metabolism and tumorigenicity of (+)- and (–)-benzo[a]pyrene 7,8-oxide. J. Biol. Chem., 255, 9067–9074.[Abstract/Free Full Text]
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  29. Levin,W., Chang,R.L., Wood,A.W., Thakker,D.R., Yagi,H., Jerina,D.M. and Conney,A.H. (1986) Tumorigenicity of optical isomers of diastereomeric bay-region 3,4-diol-1,2-epoxides of benzo[c]phenanthrene in murine tumor models. Cancer Res., 46, 2257–2261.[Abstract]
  30. Steward,A.R., Kumar,S. and Sikka,H.C. (1987) Metabolism of dibenz[a,h]acridine by rat liver microsomes. Carcinogenesis, 8, 1043–1050.[Abstract]
  31. Kumar,S., Singh,S.K., Kole,P.L., Elmarakby,S. and Sikka,H.C. (1995) Stereoselective metabolism of dibenz[a,h]acridine to bay-region diol epoxides by rat liver microsomes. Carcinogenesis, 16, 525–530.[Abstract]
Received November 29, 2000; revised February 13, 2001; accepted February 22, 2001.





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