Dl. Spencer et al., Quantitative analysis of constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1B1 expression in human lymphocytes, CANC EPID B, 8(2), 1999, pp. 139-146
Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) results in
a broad spectrum of biological responses, including altered metabolism, di
sruption of normal hormone signaling pathways, reproductive and development
al effects, and cancer. Cytochrome P450 1B1 (CYP1B1) is a dioxin-inducible
gene that is active in the formation of 4-hydroxyestradiol, a potentially g
enotoxic catechol estrogen, Therefore, the analysis of CYP1B1 in humans may
be useful in establishing relationships between dioxin exposure and advers
e health effects. In this study, we examined the expression of CYP1B1 in hu
man peripheral blood lymphocytes of unexposed individuals using a quantitat
ive reverse transcription-PCR method. Absolute CYP1B1 RNA levels varied mor
e than 30-fold in uncultured mononuclear cells obtained from 10 individuals
. In vitro treatment of mitogen-stimulated lymphocytes with TCDD for 1-5 da
ys of culture resulted in a peak induction of CYP1B1 after 3 days. The indu
ction of CYP1B1 RNA levels after 3 days of culture was dose-dependent, exhi
bited a maximum response above 10 nM TCDD, and varied greatly among differe
nt individuals. However, the half maximal dose required for this induction
was similar between individuals and comparable to that observed in the MCF-
7 and HepG2 human cell lines, These observations indicate that CYP1B1 exhib
its variable constitutive expression and is inducible in vitro by TCDD in h
uman lymphocytes and that the magnitude of induction varies within the popu
lation. These data define the suitability of CYP1B1 for use as a mechanisti
cally based biomarker in ongoing molecular epidemiological studies of human
populations exposed to dioxins and related chemicals that bind the aromati
c hydrocarbon receptor.