Roles of individual human cytochrome P-450 enzymes in the bioactivation of benzo(a)pyrene, 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and other dihydrodiol derivatives of polycyclic aromatic hydrocarbons.
Roles of individual human cytochrome P-450 enzymes in the bioactivation of benzo(a)pyrene, 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and other dihydrodiol derivatives of polycyclic aromatic hydrocarbons.
复制标题
DOI：
--
复制
发表时间：
1989-11
期刊：
影响因子：
11.2
通讯作者：
T. Shimada;Martha V. Martin;D. Pruess-Schwartz;L. Marnett;F. Guengerich
中科院分区：
文献类型：
--
作者：
T. Shimada;Martha V. Martin;D. Pruess-Schwartz;L. Marnett;F. Guengerich
在鼠伤寒沙门氏菌TA1535/pSK1002检测系统中，人肝微粒体氧化7，8-二羟基-7，8-二氢苯并(A)芘[B(A)P-7，8-二醇]生成DNA加合物和umu基因表达的产物。在用于激活的不同人肝标本中，umu反应与微粒体细胞色素P-450Nf(P-450Nf)和硝苯地平氧化水平有关，B(A)P-7，8-二醇的(+)和(-)对映体在这些和其他检测中得到了类似的结果。抗P-450NF抗体可抑制微粒体UMU反应。7，8-苯并黄酮能刺激纯化的P-450NF和人肝、肺微粒体对B(A)P-7，8-二醇依赖的umu反应。因此，P-450NF似乎是人肝脏和肺中参与B(A)P-7，8-二醇激活的主要酶。对于trans-9，10-dihydroxy-9，10-dihydrobenzo(b)fluoranthene和trans-3，4-dihydroxy-3，4-dihydro-7，12-dimethylbenz(a)anthracene，化合物的激活也得到了类似的结果，这两种化合物已知形成了高度致癌的二醇环氧化物。(+)-B(A)P-7，8-二醇氧化的主要产物是苯并(A)芘-7，8，9，10-四醇[7β，8α，9β，10 beta-tetrahydroxy-7，8，9，10-tetrahydrobenzo(a)pyrene].]的顺式异构体对人肝酶性质的研究表明，P-450NF、P-450PA、P-450J、P-450DB和P-450MP均不参与B(A)P-7，8-二醇的生成。在一组肝脏样品中7，8-二醇的形成与非那西丁O-脱乙基的相关性以及7，8-苯黄酮和抗大鼠P-450β核因子-B对该反应的部分抑制表明，参与该反应的酶可能是人的大鼠P-450β核因子-B的同系物P1-450，它既催化多环烃处理大鼠组织中B(A)P-7，8-二醇的形成及其随后的氧化。抑制剂的不同作用表明，苯并(A)芘的3-羟基化、4，5-环氧化和9，10-环氧化是由一种不同于7，8-环氧化物的酶(S)催化的。在多环烃的生物激活范式中，人类P-450酶的作用不同于啮齿动物的同系物；此外，在人类肝脏和肺中，黄酮类似乎对二醇的形成和进一步的环氧化具有相反的影响。
Human liver microsomes oxidized 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene [B(a)P-7,8-diol] to products that yield DNA adduct formation and umu gene expression in the tester system Salmonella typhimurium TA1535/pSK1002. The umu response is correlated to levels of microsomal cytochrome P-450NF (P-450NF) and nifedipine oxidation in different human liver samples used for activation, and both the (+)- and (-)-enantiomers of B(a)P-7,8-diol gave similar results in these and other assays. The microsomal umu response was inhibited by antibodies raised against P-450NF. 7,8-Benzoflavone stimulated the B(a)P-7,8-diol-dependent umu response observed with purified P-450NF and human liver and lung microsomes. Thus, P-450NF appears to be the major enzyme involved in the activation of B(a)P-7,8-diol in human liver and possibly lung. Similar results were obtained for the activation of trans-9,10-dihydroxy-9,10-dihydrobenzo(b)fluoranthene and trans-3,4-dihydroxy-3,4-dihydro-7,12-dimethylbenz(a)anthracene, compounds that are known to form highly tumorigenic diol-epoxides. The major product of the oxidation of (+)-B(a)P-7,8-diol was the cis-syn isomer of benzo(a)pyrene-7,8,9,10-tetraol[7 beta, 8 alpha, 9 beta, 10 beta-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene]. Studies on the nature of the human liver enzymes involved in the formation of B(a)P-7,8-diol [from benzo(a)pyrene] indicate that neither P-450NF, P-450PA, P-450j, P-450DB, nor P-450MP is involved. The correlation of 7,8-diol formation with phenacetin O-deethylation in a set of liver samples and the partial inhibition of the reaction by 7,8-benzoflavone and anti-rat P-450 beta NF-B suggest that the enzyme involved may be P1-450, the human ortholog of rat P-450 beta NF-B, which catalyzes both the formation of B(a)P-7,8-diol and its subsequent oxidation in tissues of polycyclic hydrocarbon-treated rats. The differential effects of inhibitors indicate that benzo(a)pyrene 3-hydroxylation, 4,5-epoxidation, and 9,10-epoxidation are catalyzed by an enzyme(s) distinct from that which forms the 7,8-epoxide. The roles of the human P-450 enzymes differ from the rodent orthologs in the paradigm for bioactivation of polycyclic hydrocarbons; further, flavones appear to have opposing effects on diol formation and further epoxidation in both human liver and lung.