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  • The hepatic constitutive levels of CYP A were minimal


    The hepatic constitutive levels of CYP1A2 were minimal and were below detectable limits in the kidney, indicating an organ-specific trend which has been reported by other groups (Hawke and Welch, 1985, Paolini et al., 1997, Parkinson, 1996, Villard et al., 1998). Retinol administration did not have an inductive effect on the this isoform, since both the catalytic activity and polypeptide levels were not increased from untreated or vehicle control. There has been some evidence demonstrating that retinoids may be involved in the regulation of the CYP1A gene. Vecchini et al. (1994) reported the presence of a retinoic Probenecid response element on the human CYP1A1 gene in normal human keratinocytes. In vivo studies demonstrated that the metabolism of benzo[a]pyrene (BaP) was inhibited following 7 days of retinyl acetate, 13-cis-retinoic acid and N-(4-hydroxyphenyl)-retinamide administration in the Sprague–Dawley rat (McCarthy et al., 1987). Conversely, Miranda et al. (1981) failed to show any significant change in BaP metabolism following dietary supplementation with retinyl palmitate (500 IU/g) in either the guinea pig or rabbit. Therefore, it appears that retinol\'s effect on CYP1A is dependent on both the species and specific retinoid administered. The hepatic microsomal catalytic activity and polypeptide levels for CYP3A were decreased in male BALB/c mice following 4 days of retinol treatment. However, retinol did not alter renal microsomal CYP3A catalytic activity. Hepatic constitutive CYP3A catalytic activity was 100-fold greater than renal CYP3A and a minimal amount of constitutive CYP3A in the kidney has been documented by other groups (Maurel, 1996, Seree et al., 1996). Additionally, our studies demonstrate that retinol does not induce renal CYP3A. However, induction of renal CYP3A is reported to occur following treatment with metalaxyl (Paolini et al., 1997). Our observation regarding a decrease in hepatic CYP3A is contrary to findings in other species. Various groups have documented an induction of CYP3A following retinol treatment. Murray et al. (1991) reported a 158% increase in the polypeptide levels of CYP3A in rats fed a diet supplemented with 25 IU/g of retinol for 15 weeks. Rabbits fed a diet containing 500 IU retinyl palmitate for 7 weeks demonstrated an increase in 7-ethoxycoumarin deethylase activity, a non-specific measure of CYP3A activity (Miranda and Chhabra, 1981). Furthermore, Badger et al. (1998) reported a 132% increase in progesterone 6β-hydroxylation following 1 day of retinol treatment in rats. However, these values returned to within normal limits 48 h following retinol and by 96 h CYP3A catalytic activity had dropped to below control levels (Badger et al., 1998). It appears from these three studies that mice respond distinctly compared to other species following retinol administration. Therefore, the differences seen between our work and that of other laboratories, is likely a species-specific response. In rats it would appear that retinoids induce CYP2E1 or CYP3A and in guinea pigs retinol induces CYP2E1, but in mice retinol has no significant effect on the catalytic activity or polypeptide levels of CYP2E1 or CYP1A2. Retinol supplementation did however result in a significant decrease of both the catalytic activity and polypeptide levels of hepatic CYP3A, a result not seen in previously published rat studies. No changes were observed in the catalytic activity or polypeptide levels of renal CYP2E1 following retinol supplementation, a finding not previously documented in the literature. These results show that the organ-specific response in potentiation of paracetamol-induced toxicity is not due to differential CYP450 induction and, therefore, potentiation of paracetamol hepatotoxicity must be produced through another mechanism. This conclusion is based on the fact that CYP450 activities were measured 24 h following retinol pretreatment, which would detect changes in CYP450 at a time-point pertinent to paracetamol bioactivation.