In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 75, No. 7 ( 1978-07), p. 3123-3127
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.75.7.3123
Sprache:
Englisch
Verlag:
Proceedings of the National Academy of Sciences
Publikationsdatum:
1978
ZDB Id:
209104-5
ZDB Id:
1461794-8
SSG:
11
SSG:
12
