Induction of Cytochrome P4501A1 in Haemopoietic Stem Cells by Hydroxylated Metabolites of Benzene.
The ability of various metabolites of benzene to regulate the expression of cytochrome P-450 (CYP)1A1 mRNA in human haemopoietic cells was investigated. CYP1A1 mRNA was quantified using a Northern blot technique and high stringency hybridization with a (32)P-labelled cDNA probe. Benz[a]anthracene (BA, 1 or 10 mum), used as a positive control, induced CYP1A1 mRNA in two out of three human leukaemic haemopoietic stem cell lines (positive: KG-1, U937; negative: HL-60), as well as in long-term bone marrow cultures established from healthy volunteers. In KG-1 and U937 cells, CYP1 Al mRNA induction was studied in the presence of the benzene metabolites, hydroquinone (HQ), p-benzoquinone (BQ), phenol (PHE) and catechol (CAT). HQ and BQ induced CYP1A1 mRNA when added at concentrations of 100 nm or more; CAT was active at a concentration of 1 mum, whereas PHE had almost no effect, even at the highest concentration used (1 mum). Maximum mRNA levels induced by 1 mum HQ were seen at 6 and 12 hr after addition of inducers, and induction was detectable for at least 48 hr. Little, if any, cellular toxicity was seen in clonogenic assays of KG-1 cells at concentrations of maximum induction. In conclusion, CYP1A1 mRNA induction was demonstrated in haemopoietic cells; inducers for CYP1A1 were not only a polycyclic aromatic hydrocarbon (BA), but also, unexpectedly, hydroxylated metabolites of benzene.
Henschler
R
R
Department of Hematology, Freiburg University Medical Center, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
Glatt
H R
HR