Dose-response studies on the induction of liver cytochromes P4501A1 and 1B1 by polycyclic aromatic hydrocarbons in arylhydrocarbon-responsive C57BL/6J mice

Abstract

1. To determine the biological effects of 23 polycyclic aromatic hydrocarbons (PAHs) and 3,4,3',4'-tetrachlorobiphenyl, the dose-response studies of the induction of CYP1-dependent xenobiotic oxidation activities by these chemicals in liver microsomes of C57BL/6J mice were studied. 2. In arylhydrocarbon-responsive C57BL/6J mice, the liver microsomal xenobiotic oxidation with substrates of 7-ethoxyresorufin, 7-ethoxycoumarin, (+/-)-benzo[a]pyrene-7,8-diol, dibenzo[a, pyrene-11,12-diol and 2-amino-3,5-dimethylimidazo[4,5-f]quinoline increased by increasing the doses of PAHs to mice, particularly when the PAHs that have been reported to be carcinogenic in experimental animals were used. In arylhydrocarbon receptor-knockout mice, there were no increases in liver microsomal 7-ethoxyresorufin O-deethylation activities nor in liver mRNA levels of CYP1A1, 1A2 and 1B1 by these chemicals. 3. Of the chemicals examined, benzo[k]fluoranthene, benzo[b]fluoranthene, benzo[j]-fluoranthene, 3-methylcholanthrene, dibenz[a,h]anthracene, dibenz[a,c]anthracene and 3,4,3',4'-tetrachlorobiphenyl were potent inducers of the induction of liver microsomal 7-ethoxyresorufin O-deethylation in mice. 4. Other PAHs such as 5-methylchrysene, benzo[a]pyrene, dibenzo[a,l]pyrene, dibenz[a,j]acridine, benzo[a]anthracene and 7,12-dimethylbenz[a]anthracene moderately induced 7-ethoxyresorufin O-deethylation activities in mice. PAHs reported to be weak or less carcinogenic in experimental animals did not induce the xenobiotic oxidation activities of CYP1A1 and 1B1 in the mice. 5. The results suggest that induction of liver microsomal CYP1-dependent xenobiotic oxidation activities is a good tool in determining the potencies of carcinogenic PAHs in arylhydrocarbon-responsive C57BL/6J mice.

For Dioxin-induced Birth Defects, Mouse or Human CYP1A2 in Maternal Liver Protects whereas Mouse CYP1A1 and CYP1B1 Are Inconsequential

“…We have previously generated a hCYP1A1_1A2 BAC-transgenic mouse line (63). The tissue-specific expression pattern and inducibility of the human CYP1A genes in these mice suggest that sufficient genomic regulatory sequences are present in the 180-kb BAC to direct authentic expression of these genes, similar to what is observed with the human or mouse endogenous CYP1A genes (77)(78)(79)(80). We generated these mice primarily because of reported catalytic differences between rodent and human CYP1A2, and in response to the need for a better model for human xenobiotic metabolism and risk assessment in laboratory animals.…”

Up-regulation of CYP1A/B in rat lung and liver, and human liver precision-cut slices by a series of polycyclic aromatic hydrocarbons; association with the Ah locus and importance of molecular size

“…When CYP1 was monitored at the activity level, using ethoxyresorufin as probe substrate, a marked difference in the ability of the six PAHs to elevate this activity in rat liver slices was noted. (Shimada et al, 2003). Moreover, the present observations make a case for using precision-cut liver slices for assessing induction potential of slices, rather than in vivo studies, which not only allow the facile use of many concentrations but also minimise the number of animals.…”

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

“…The extents of induction of hepatic mRNAs of CYP1A1, 1A2 and 1B1 were also determined in AhR +/+ mice that had been treated intraperitoneally with each of 23 PAHs or 3,4,3′,4′-tetrachlorobiphenyl at a dose level of 100 mg/kg bw (Shimada et al, 2003b). Both CYP1A1 and 1B1 were highly induced by the PAHs that are potent carcinogens in experimental animals Pelkonen & Nebert, 1982;Shimada et al, 2002Shimada et al, , 2003a.…”