TY - JOUR
T1 - Regio- and stereoselectivity of various forms of purified cytochrome P-450 in the metabolism of benzo[a]pyrene and (-)trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene as shown by product formation and binding to DNA
AU - Deutsch, J.
AU - Leutz, J. C.
AU - Yang, S. K.
AU - Gelboin, H. V.
AU - Chiang, Y. L.
AU - Vatsis, K. P.
AU - Coon, M. J.
PY - 1978
Y1 - 1978
N2 - Highly purified cytochromes P-450LM2 and P-450LM4 and partially purified P-450LM1, P-450LM3b, and P-450LM7 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-450LM2 is more active than P-450LM4 in the metabolism of BzP and in its conversion to products that bind to DNA. In contrast, P-450LM4 is more active than P-450LM2 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-450LM2 and 0.3 for P-450LM4; P-450LM1, P-450LM3b, and P-450LM7 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-450LM4, whereas the other preparations showed less selectivity. The ratio of diol-epoxide I to diol-epoxide II ranges from 0.3 for P-450LM7 to 11 for P-450LM4. The substrate specificity and regio- and stereoselectivity 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.
AB - Highly purified cytochromes P-450LM2 and P-450LM4 and partially purified P-450LM1, P-450LM3b, and P-450LM7 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-450LM2 is more active than P-450LM4 in the metabolism of BzP and in its conversion to products that bind to DNA. In contrast, P-450LM4 is more active than P-450LM2 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-450LM2 and 0.3 for P-450LM4; P-450LM1, P-450LM3b, and P-450LM7 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-450LM4, whereas the other preparations showed less selectivity. The ratio of diol-epoxide I to diol-epoxide II ranges from 0.3 for P-450LM7 to 11 for P-450LM4. The substrate specificity and regio- and stereoselectivity 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.
UR - http://www.scopus.com/inward/record.url?scp=0018139858&partnerID=8YFLogxK
U2 - 10.1073/pnas.75.7.3123
DO - 10.1073/pnas.75.7.3123
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:0018139858
VL - 75
SP - 3123
EP - 3127
JO - Unknown Journal
JF - Unknown Journal
IS - 7
ER -