Rice J E, Weyand E H, Geddie N G, DeFloria M C, LaVoie E J
Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595.
Cancer Res. 1987 Dec 1;47(23):6166-70.
The metabolism of benzo[j]fluoranthene (BjF) in vivo in mouse skin was investigated. trans-4,5-Dihydro-4,5-dihydroxybenzo[j]fluoranthene (BjF-4,5-diol) and trans-9,10-dihydro-9,10-dihydroxybenzo[j]fluoranthene (BjF-9,10-diol) have been identified as major metabolites. In addition, 4- and 10-hydroxybenzo[j]fluoranthene and benzo[j]fluoranthen-4,5-dione have been tentatively identified among the metabolites formed in vivo in mouse skin. The enantiomeric purity of the metabolic dihydrodiols of BjF as formed in vivo in mouse skin was determined. The major enantiomer of BjF-4,5-diol was present in 57-62% enantiomeric excess while that of BjF-9,10-diol was present in 66-71% enantiomeric excess. In each case the later-eluting enantiomer on chiral stationary-phase high performance liquid chromatography predominated. The tumor-initiating activity of trans-2,3-dihydro-2,3-dihydroxybenzo[j]fluoranthene (BjF-2,3-diol), BjF-4,5-diol, BjF-9,10-diol, and BjF was evaluated on the skin of female CD-1 mice. As a total initiation dose of 3 mumol/mouse BjF-4,5-diol resulted in a 100% incidence of tumor-bearing mice with 5.0 tumors/mouse. In comparison, BjF-9,10-diol elicited a 60% incidence of tumor-bearing mice with 1.7 tumors/mouse, while BjF-2,3-diol was inactive. At the same dose, BjF gave rise to a 90% incidence of tumor-bearing mice with 7.8 tumors/mouse. At a 1-mumol dose, BjF-4,5-diol induced a 78% incidence of tumor-bearing mice with 4.3 tumors/mouse while BjF gave rise to a 70% tumor incidence with 3.4 tumors/mouse while BjF gave rise to a 70% tumor incidence with 3.4 tumors/mouse. These studies indicate that while BjF-9,10-diol could contribute to the overall tumorigenic activity of BjF in mouse skin, BjF-4,5-diol is a more potent tumor initiator in the target tissue.
研究了苯并[j]荧蒽（BjF）在小鼠皮肤中的体内代谢情况。反式-4,5-二氢-4,5-二羟基苯并[j]荧蒽（BjF-4,5-二醇）和反式-9,10-二氢-9,10-二羟基苯并[j]荧蒽（BjF-9,10-二醇）已被确定为主要代谢产物。此外，在小鼠皮肤体内形成的代谢产物中，还初步鉴定出了4-羟基苯并[j]荧蒽、10-羟基苯并[j]荧蒽和苯并[j]荧蒽-4,5-二酮。测定了小鼠皮肤体内形成的BjF代谢二氢二醇的对映体纯度。BjF-4,5-二醇的主要对映体的对映体过量为57%-62%，而BjF-9,10-二醇的主要对映体的对映体过量为66%-71%。在每种情况下，手性固定相高效液相色谱上后洗脱的对映体占主导。评估了反式-2,3-二氢-2,3-二羟基苯并[j]荧蒽（BjF-2,3-二醇）、BjF-4,5-二醇、BjF-9,10-二醇和BjF对雌性CD-1小鼠皮肤的肿瘤启动活性。作为3 μmol/只小鼠的总启动剂量，BjF-4,5-二醇导致荷瘤小鼠的发生率为100%，每只小鼠有5.0个肿瘤。相比之下，BjF-9,10-二醇引起荷瘤小鼠的发生率为60%，每只小鼠有1.7个肿瘤，而BjF-2,3-二醇无活性。在相同剂量下，BjF导致荷瘤小鼠的发生率为90%，每只小鼠有7.8个肿瘤。在1 μmol剂量下，BjF-4,5-二醇诱导荷瘤小鼠的发生率为78%，每只小鼠有4.3个肿瘤，而BjF导致肿瘤发生率为70%，每只小鼠有3.4个肿瘤。这些研究表明，虽然BjF-9,10-二醇可能对BjF在小鼠皮肤中的整体致瘤活性有贡献，但BjF-4,5-二醇在靶组织中是一种更有效的肿瘤启动剂。
