Effects of Tin-Porphyrins on Developmental Changes in Hepatic Cytochrome P450 Content, Selected P450-Dependent Drug-Metabolizing Enzyme Activities and Brain Glutathione Levels in the Newborn Rat

Abstract

Sn-mesoporphyrin is considerably more effective than Sn-protoporphyrin in inhibiting bilirubin production in vivo, in the experimental animal. In this study the effects of Sn-mesoporphyrin, administered in doses ranging from 1 to 20 μmol/kg b.w., on the developmental patterns of hepatic cytochrome P450 content and cytochrome P450-dependent drug metabolism in rat neonates were examined at various time points during the 5-week period immediately after birth. No detrimental alterations in cytochrome P450 content or in cytochrome P450-dependent drug metabolism were observed. In addition no deleterious effects were noted on total glutathione content in brain of Sn-mesoporphyrin-treated animals. After single doses of Sn-protoporphyrin of 20, 50 or 100 μmol/kg b.w. were administered at birth, transient decreases in hepatic cytochrome P450 content (days 1 and 2), and ethylmorphine demethylase (days 2 and 5) and 7-ethoxycoumarin deethylase (days 1 2 and 5) activities were observed in the period immediately after birth. However no sustained alterations in the developmental patterns of these enzymes were observed even at the highest dose (100 μmol/kg b.w.) of Sn-protoporphyrin administered. These findings indicate that in the doses utilized in this study both metalloporphyrins have no long-term effects on cytochrome P450-dependent drug metabolism. Furthermore, in doses up to 20 μmol/kg b.w., neither compound produced any short-term effects on hepatic cytochrome P450 content or functional activity in newborn rats.

Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity.

“…To further ascertain the characteristics of the expressed HO protein, we tested the effect of Sn-mesoporphyrin, a potent inhibitor of HO activity, on microsomal preparations from both nontransfected and transfected cells. Addition of 5 ,uM Sn-mesoporphyrin to cell preparations inhibited the enzyme activity by -90% and -75% (P < 0.001) in both control and transfected cells, respectively (Table 1), as has been demonstrated with the normal and induced mammalian HO (24)(25)(26)(27)(28).…”

Protective Properties of Tin‐ and Manganese‐Centered Porphyrins Against Hydrogen Peroxide‐Mediated Injury in Rat Astroglial Cells

“…However, efforts to detect changes in iron using Perl' s stain or 3,3 '-diaminobenzidine-enhanced Pen's stain have been unsuccessful to date, most likely because of the low sensitivity of these methods (data not shown). Our data do not preclude other potentially important protective mechanisms, including alterations in cytochrome P450 and cytochrome P450-dependent enzymes (Drummond et al, 1989;Sessa et al, 1989) and the inhibition of soluble guanylyl cyclase, a property of both metalloporphyrin heme oxygenase inhibitors (Ignarro et al, 1984;Luo and Vincent, 1994) and MnTMPyP (Pfeiffer et al, 1998). Protection against H2O2 by combined tin-mp and MnTMPyP was partial, suggesting that cell injury from H2O2 involves mechanisms not sensitive to either tin-mp or MnTMPyP.…”

Metalloporphyrins – An Update

“…Mps have been found to also interact with other heme-containing enzyme systems, such as nitric oxide synthase (NOS; Luo and Vincent, 1994; Meffert et al, 1994), soluble guanylyl cyclase (sGC; Ignarro et al, 1984; Grundemar and Ny, 1997), and cytochrome P450 (CYP 450 ; Drummond et al, 1989; Trakshel et al, 1992). They also affect hematopoiesis (Maines and Trakshel, 1992b; Lutton et al, 1997), steroidogenesis (Maines and Trakshel, 1992b; Drummond et al, 1996), and the iron status of the body (Kappas et al, 1993; Berglund et al, 1999).…”

“…Others showed that hepatic CYP 450 content is only transiently altered after administration of SnPP or SnMP to neonatal rats and does not persist into adulthood. The studies used several different doses and application routes to adult or neonatal rats (Drummond et al, 1989, 1996). Overall, SnPP and SnMP decrease CYP 450 activity and thus affect CYP 450 -dependent enzymes of adrenal synthesis and drug metabolism in animal models.…”