In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 75, No. 7 ( 1978-07), p. 3123-3127
Abstract:
Highly purified cytochromes P -450 LM2 and P -450 LM4 and partially purified P -450 LM1 , P -450 LM3b , and P -450 LM7 from rabbit liver microsomes exhibit different catalytic activities in the metabolism of benzo[ a ]pyrene (BzP) and (-)- trans -7,8-dihydroxy-7,8-dihydrobenzo[ a ]pyrene [(-) trans -7,8-diol] in a reconstituted enzyme system. The two highly purified cytochromes also exhibit differences in the activation of BzP and (-) trans -7,8-diol to intermediates that bind to DNA, as well as in the stereoselective conversion of (-) trans -7,8-diol to the highly mutagenic and carcinogenic diol-epoxides r -7, t -8-dihydroxy- t -9,10-oxy-7,8,9,10- tetrahydrobenzo[ a ]pyrene (diol-epoxide I) and r - 7, t - 8 - dihydroxy - c - 9,10 - oxy - 7,8,9,10 - tetrahydrobenzo[ a ]pyrene (diol-epoxide II). P -450 LM2 is more active than P -450 LM4 in the metabolism of BzP and in its conversion to products that bind to DNA. In contrast, P -450 LM4 is more active than P -450 LM2 in the metabolism of (-) trans -7,8-diol and in its conversion to products that bind to DNA. The ratio of activity (percent substrate metabolized) with BzP relative to that with (-) trans -7,8-diol is 21 for P -450 LM2 and 0.3 for P -450 LM4 ; P -450 LM1 , P -450 LM3b , and P -450 LM7 gave intermediate ratios. Marked stereoselectivity in the oxygenation of the (-) trans -7,8-diol to the highly mutagenic and putatively carcinogenic diol-epoxides I and II was observed with P -450 LM4 , whereas the other preparations showed less selectivity. The ratio of diolepoxide I to diol-epoxide II ranges from 0.3 for P -450 LM7 to 11 for P -450 LM4 . The substrate specificity and regio- and stereo-selectivity of the different forms of cytochrome P -450 may regulate the balance between activation and detoxification pathways of BzP and therefore determine the susceptibility of individual tissues, strains, and species to the carcinogenic action of BzP.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.75.7.3123
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1978
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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