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PubMed1989

Comparative studies on the inducing effects of cobalt chloride and co-protoporphyrin on hepatic ornithine decarboxylase and heme oxygenase in rats.

Co-protoporphyrin, like Co2+, produced a significant and persistent induction of hepatic ornithine decarboxylase (ODC) as well as its known inducing effect on heme oxygenase and the decreasing effects on drug-metabolizing enzymes. The induction of ODC and heme oxygenase by Co-protoporphyrin occurred dose-dependently with the lowest effective dose of 6.25 mumol/kg. Although Co-protoporphyrin produced similar effects on ODC and heme oxygenase to Co2+, there were differences in the mode of ODC induction. In particular, pretreatment with diethyl maleate failed to augment the induction of ODC by Co-protoporphyrin. Moreover, multiple administrations of Co2+, but not Co-protoporphyrin, caused super-additive induction of ODC to about 1000-fold over the controls. This super-additive induction of ODC by Co2+ was dependent on the doses and time intervals between two administrations. In parallel with a large induction of ODC evoked by two administrations of Co2+, hepatic putrescine content was increased markedly, while spermine content was decreased as compared to the control levels. Pretreatment with Co2+ led to super-additive induction of ODC by subsequent administration of the metal ion itself or diethyl maleate, but not by other ODC inducers, such as Co-protoporphyrin and thioacetamide, and not by subsequent partial hepatectomy. Under these experimental conditions, the magnitudes of heme oxygenase induction were similar. ODC induced by two doses of Co2+ was insensitive to exogenous putrescine, but sensitive to alpha-difluoromethylornithine and 1,3-diaminopropane. These findings add new insight into the effects of Co2+ and Co-protoporphyrin on hepatic polyamine metabolism; and the results suggest that the metal ion could cause extensive derangement of the ODC regulatory system in a manner different from the metalloporphyrin.

Animals↗

PubMed1983

Induction of heme oxygenase and inhibition of delta-aminolevulinic acid synthetase of rat liver by thioacetamide and thioacetamide-S-oxide.

Thioacetamide and one of its metabolite, thioacetamide-S-oxide, were shown to increase heme oxygenase and to inhibit delta-aminolevulinic acid (ALA) synthetase when administered in vivo to male rats. Concomitant with the increase of heme oxygenase and the decrease of ALA synthetase, concentration of cytochrome P-450 and drug metabolizing enzyme activities were decreased by in vivo administration of thioacetamide and thioacetamide-S-oxide to rats. The results of these studies indicate that thioacetamide and thioacetamide-S-oxide are not only inhibitor of ALA synthetase, but also inducer of heme oxygenase in rats. Further, thioacetamide-S-oxide is generally more effective than thioacetamide with respect to the effects on cytochrome P-450, ALA synthetase and heme oxygenase.

5-Aminolevulinate Synthetase↗

PubMed2002

Interaction of heme with nitroxyl or nitric oxide amplifies heme oxygenase-1 induction: involvement of the transcription factor Nrf2.

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme, the expression of which is highly sensitive to induction by pro-oxidant stimuli including the substrate heme and reactive oxygen species. Conceptually, the perception that HO-1 plays a key role in response to oxidative damage is paralleled by evidence showing high expression of HO-1 in a variety of cell systems challenged with nitric oxide (NO) or NO-derivatives, thus revealing a potential biological function for HO-1 against nitrosative stress. In this study, we report that exposure of cardiac cells to hemin (5-20 microM) in combination with compounds that liberate nitroxyl (HNO/NO-) or release NO significantly potentiates HO-1 mRNA and protein expression leading to a remarkable increase in heme oxygenase activity under both normoxic and hypoxic conditions. The amplification of the heme oxygenase pathway appears to involve a direct interaction between heme and the NO groups, as the ability of both NO(-)- and NO-releasing agents to induce HO-1 is totally lost by their pre-incubation for 1 hr in complete medium prior to cell treatment but is highly preserved by addition of hemin during the preincubation step. In addition, we show that the redox-sensitive transcription factor Nrf2 is highly expressed in the nuclear fraction of cells exposed to the NO- generator and that this effect is totally abolished by the presence of N-acetyl-L-cysteine. Interestingly, the expression of Nrf2 is gradually intensified by treating cells with a combination of the NO- releaser and increasing concentrations of hemin. Thus, a strict parallelism exists between the extent of HO-1 induction and expression of Nrf2 elicited by the heme-NO interaction. We propose that modification of the iron protoporphyrin centers by NO groups to modulate HO-1 expression might be regarded as a molecular switch to maximize heme oxygenase enzymatic activity and consequently mitigate the redox imbalance imposed by oxidative and nitrosative stress.

Acetylcysteine↗

PubMed1991

Involvement of mono-oxygenases as a major mechanism of deltamethrin-resistance in larvae of three species of mosquitoes.

Role of mono-oxygenases as a mechanism of resistance to the synthetic pyrethroid, deltamethrin in the larvae of Culex quinquefasciatus Say, Aedes aegypti L. and Anopheles stephensi Liston developed by laboratory selections with deltamethrin, DDT or deltamethrin and the synergist, piperonyl butoxide (PBO) in the ratio of 1:5, was investigated. There was a significant correlation with mono-oxygenase activity and larval LC50 to deltamethrin in various strains of all the three species. In addition, the activity of glucose-6-phosphate dehydrogenase (G6PD), the main NADPH generating enzyme for mono-oxygenases, also showed enhanced activity in deltamethrin and DDT-selected strains. The present data, therefore, clearly suggest that deltamethrin resistance in the larvae of Cx. quinquefasciatus, Ae. aegypti and An. stephensi is mainly due to the detoxification of deltamethrin by microsomal mono-oxygenases. High activity of G6PD observed in DDT-selected strains seems to be related to its role as a rate-limiting enzyme in GSH-dependent dehydrochlorination of DDT.

Aedes↗

PubMed1986

Alterations in microsomal drug metabolism and heme oxygenase activity in isolated hepatic parenchymal and sinusoidal cells in Murphy-Sturm lymphosarcoma-bearing rats.

Previous studies have demonstrated that Murphy-Sturm lymphosarcoma-bearing rats have significantly decreased hepatic microsomal cytochrome P-450 and NADPH-cytochrome c reductase activity, a consequent decreased capacity for oxidative microsomal drug metabolism, and increased microsomal heme oxygenase activity. Splenic microsomes obtained from tumor-bearing rats did not display similar changes. To define the cellular locus of these changes, preparations of hepatic parenchymal and hepatic sinusoidal cells were obtained from control and Murphy-Sturm lymphosarcoma-bearing rats and examined for alterations in microsomal parameters of drug metabolism and heme oxygenase. In hepatic parenchymal cell populations, heme oxygenase activity was significantly increased in tumor-bearing rats (0.046 nmol/mg/min vs. 0.019 nmol/mg/min, control, p less than 0.01) while other microsomal parameters were all significantly decreased in activity (cytochrome P-450, 0.25 nmol/mg vs 0.70 nmol/mg, control, p less than 0.001; NADPH-cytochrome c reductase, 24.4 nmol/mg/min vs 42.6 nmol/mg/min, control, p less than 0.005; benzo(a) pyrene hydroxylase, 0.230 nmol/mg/min vs. 0.518 nmol/mg/min, control, p less than 0.001). These results are similar to those obtained with microsomes from whole liver. Conversely, while hepatic sinusoidal cell preparations also demonstrated increased heme oxygenase activity (0.134 nmol/mg/min vs 0.079 nmol/mg/min, control, p less than 0.01), all other hepatic sinusoidal cell microsomal parameters were not appreciably altered in tumor-bearing animals. The results indicate that the major effect of the tumor-bearing state on hepatic microsomal heme and drug metabolism is on the parenchymal cell, and not the sinusoidal cell population.

Animals↗

PubMed1988

Induction of heme oxygenase in rat hepatoma cells by exposure to heavy metals and hyperthermia.

Treatment of rat hepatoma dRLh-84 cells with sodium arsenite, cadmium chloride and cobalt chloride resulted in marked induction of protein with a molecular mass of 32 kDa. To examine the possibility that the induced 32 kDa protein may be heme oxygenase, the enzyme activity was measured, and then the activity in the cells increased by these metals, and heat shock treatments. Immunoblot analysis showed that the induction of 32 kDa protein reacted with anti-heme oxygenase antibody occurred by the treatments. Northern blot analysis confirmed that the induction of heme oxygenase by arsenite, cadmium and cobalt, and by hyperthermia was regulated at transcriptional level. These findings support the hypothesis that the 32 kDa stress protein induced by heavy metals in rat hepatoma cells is heme oxygenase.

Animals↗

PubMed1984

Tissue distribution and disposition of tin-protoporphyrin, a potent competitive inhibitor of heme oxygenase.

Tin(Sn)-protoporphyrin is a potent competitive inhibitor of heme oxygenase and can also suppress naturally occurring or experimentally induced hyperbilirubinemia in animals. In this study we examined the plasma clearance of Sn-protoporphyrin, its persistence in tissues and the time course of heme oxygenase inhibition up to 7 days after administration of doses up to 50 mumol/kg b.w. to adult male rats. After s.c. doses the metalloporphyrin was rapidly and almost completely absorbed. Initial plasma clearance was log-linear with a T 1/2 of approximately 3 h after either i.v. or s.c. administration. Levels of Sn-protoporphyrin in most tissues rose during the first 2 h and persisted for up to 7 days. Concentrations were highest in kidney and liver, were considerably lower in spleen, lung, intestine, adrenal and testes, and as Sn-protoporphyrin concentrations in plasma declined, concentrations in these tissues eventually exceeded simultaneous plasma concentrations. This suggests a varying degree of uptake and binding of the metalloporphyrin in these tissues. There was little or no uptake of Sn-protoporphyrin in heart, brain and red cells. Markedly decreased heme oxygenase activity in liver, kidney and spleen persisted as did Sn-protoporphyrin up to 7 days. The total amount of Sn-protoporphyrin present in tissues and excreta was a fairly constant fraction of the dose (approximately 50%) at time intervals up to 7 days after injection. These results indicate that single doses of Sn-protoporphyrin are rapidly cleared from plasma and persist in tissues and potently inhibit heme oxygenase activity for prolonged periods.

Animals↗

PubMed1982

Purification and properties of bovine spleen heme oxygenase. Amino acid composition and sites of action of inhibitors of heme oxidation.

Microsomal heme oxygenase has been purified from bovine spleen to homogeneity using DEAE-cellulose chromatography, initial hydroxyapatite chromatography, gel filtration, and repeat hydroxyapatite chromatography. The purified enzyme showed a single protein band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular weight of congruent to 31,000. It had a Km for heme of 0.93 microM, a specific activity of 6770 units/mg of protein, and a turnover number of 3.5 mol/mol of enzyme/min. Amino acid analysis of the purified enzyme revealed an abundance of glutamine and glutamic acid residues, a log tryptophan content (2 tryptophan residues/mol of enzyme), and four free sulfhydryl groups, only two of which were accessible to sulfhydryl (--SH) inactivating reagents without unfolding of the protein. Consistent with these findings, the purified enzyme had a relatively low extinction coefficient at 280 nm (E11%cm = 8.12) and was relatively resistant to inactivation by --SH inactivating reagents. NADPH-cytochrome c reductase from bovine liver was purified to homogeneity and biliverdin reductase from bovine spleen was partially purified. The heme oxygenase system was reconstituted from preparations of all three purified enzymes and, utilizing this reconstituted system, the specific sites of the inhibitory actions of --SH inactivating reagents, inorganic metals, and metalloporphyrins on the heme degrading sequence of reactions were examined. Sn-, Co-, Zn-, and Mn-protoporphyrin strongly inhibited heme degradation in a competitive manner. The Ki values for Sn-, Co-, and Zn-protoporphyrin were determined to be 0;033, 0.082, and 0.13 microM, respectively. Mg-, Ni-, and Cu-protoporphyrin had little effect on heme degradation by the reconstituted system. Metals such as Pt2+ and Hg2+ strongly inhibited the activity of the reconstituted heme oxygenase system, but the principal site of action of these metals was at the level of NADPH-cytochrome c reductase or biliverdin reductase. Similarly --SH inactivating reagents, such as p-chloromercuribenzoate, 5,5'-dithiobis-(2-nitrobenzoate), or N-ethylmaleimide inhibited the reaction catalyzed by the reconstituted heme oxygenase system principally by inhibiting the activity of NADPH-cytochrome c reductase.

Amino Acids↗

PubMed1995

Differential heme oxygenase induction by stannous and stannic ions in the heart.

Heme oxygenase is the rate-limiting enzyme in heme catabolism, and is induced by oxidative stress, foreign and endogenous chemicals, and many trace elements and heavy metals. This study examined the effect of the oxidative state of the heavy metal tin, on heme oxygenase-1 induction in cardiac tissue. Subcutaneous administration of stannous and stannic chloride failed to induce the enzyme in this tissue. Atomic absorption spectroscopy revealed the absence of tin in the heart cells. Investigation of several metal formulations showed that both stannous and stannic citrate were able to enter the bloodstream from the injection site and into heart tissue. Northern blot analysis revealed that heme oxygenase-1 mRNA was elevated several-fold in rat hearts from animals which received either stannous or stannic citrate, and that mRNA levels corresponded with the increase in enzyme activity. The presence of citrate facilitated the transport of the tin ion into the blood stream and possibly across cardiac cell membrane. The stannous ion was more potent as an inducer of heme oxygenase than was the stannic ion.

Analysis of Variance↗

PubMed2006

Heme oxygenase and cyclooxygenase in the central nervous system: a functional interplay.

Heme oxygenase (HO) and cyclooxygenase (COX) are two hemeproteins involved in the regulation of several functions in the nervous system. Heme oxygenase is the enzyme responsible for the degradation of heme into ferrous iron, carbon monoxide (CO), and biliverdin, the latter being further reduced in bilirubin (BR) by biliverdin reductase. Heme oxygenase-derived CO is a gaseous neuromodulator and plays an important role in the synaptic plasticity, learning and memory processes, as well as in the regulation of hypothalamic neuropeptide release, whereas BR is an endogenous molecules with antioxidant and anti-nitrosative activities. Cyclooxygenase is considered a pro-inflammatory enzyme as free radicals and prostaglandins (PGs) are produced during its catalytic cycle. Although PGs are also involved in a variety of physiologic conditions including angiogenesis, hemostasis, or regulation of kidney function, upregulation of COX and increase in PGs levels are a common feature of neuroinflammation. In the brain, a functional interplay exists between HO and COX. Heme oxygenase regulates COX activity by reducing the intracellular heme content or by generating CO, which stimulates PGE(2) release. Increased levels of PGs, free radicals, and the associated oxidative stress serve in the brain as a trigger for the induction of HO isoforms which increases cellular antioxidant defenses to counteract oxidative damage. The importance of the interaction between HO and COX in the regulation of physiologic brain functions, and its relevance to neuroprotective or neurodegenerative mechanisms are discussed.

Animals↗

PubMed1995

Modulation of heme oxygenase activity in rat brain and spleen by inhibitors and donors of nitric oxide.

The capacity of nitric oxide to activate or inhibit metalloprotein-containing enzymes underlies many of its biological actions. Heme oxygenase, involved in a variety of biological processes, does not contain heme but utilises it as a substrate. The substrate for nitric oxide, L-arginine (0.1-10mM), but not D-arginine, decreased heme oxygenase activity in rat brain homogenates. The arginine analogue L-NAME (0.1-10mM) increased activity in the same tissue. In spleen homogenates where endogenous nitric oxide activity is lower than in brain, these compounds had no effect. The nitric oxide donor sodium nitroprusside (0.001mM-10mM) reduced heme oxygenase activity in both brain and spleen. These results suggest that biological effects attributed to modulation of nitric oxide synthase may act via heme oxygenase.

Animals↗

PubMed1996

Expression of heme oxygenase and inducible nitric oxide synthase mRNA in human brain tumors.

Heme oxygenase-1, a key enzyme in heme catabolism, and inducible nitric oxide synthase (iNOS) are responsible for production of carbon monoxide and nitric oxide (NO), respectively. Expression of each enzyme has been shown to be modulated by heme and NO, raising a possibility for the coordinated regulation of the two enzymes. We therefore analyzed the expression levels of both mRNA in humans using brain tumors. Either heme oxygenase-1 or iNOS mRNA was expressed at higher levels in brain tumors compared to the brain tissue, but their expression levels were not apparently correlated. In the brain tumor cell lines, treatment with cytokines increased the expression of iNOS mRNA but not heme oxygenase-1 mRNA, whereas treatment with an NO donor increased the expression of heme oxygenase-1 mRNA but not iNOS mRNA. These results suggest the separate regulation of expression of both enzyme mRNA in humans.

Adult↗

PubMed1976

Myo-inositol oxygenase from oat seedlings.

Enzyme preparations from oat seedlings showing the activity of myo-inositol oxygenase (E.C.1.13.99.1) have been described previously. In contrast to myo-inositol oxygenase preparations from other sources, e.g. rat kidney or yeast, the oat enzyme seemed to exhibit a somewhat less stringent activity, acting on other inositols and inositol methyl ethers as well as on myo-inositol. By purification of the enzyme present in the extract from oat seedlings with the help of an affinity gel specific for enzymes acting on myo-inositol a homogeneous enzyme preparation was obtained, which shows the same strict specificity as the myo-inositol oxygenase from other sources. It has a molecular weight of 62,000 and tends to aggregate to oligomers (up to tetramers) under physiological pH-values; in more alkaline media dissociation to monomers is observed. The action on the other inositols and inositol methyl ethers is apparently due to one or more other enzymes, which are also adsorbed on the affinity gel, but can be separated from the myo-inositol oxygenase by elution with increasing concentrations of myo-inositol.

Edible Grain↗

PubMed1991

Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity and to iron ion-reducing ability.

We investigated the ability of various plant flavonoids (a) to inhibit 5-lipoxygenase and cyclooxygenase activities in rat peritoneal leukocytes, (b) to inhibit lipid peroxidation in rat liver microsomes, and (c) to stimulate DNA degradation caused by the antibiotic bleomycin in the presence of ferric ions. These compounds were compared with a range of synthetic phenolic substances including carnosol, vanillin, vitamin E and its analogue trolox c. The flavonoids were potent inhibitors of non-enzymatic peroxidation in membranes but this was not significantly correlated with their ability to inhibit either pathway of eicosanoid synthesis, suggesting that their mode of inhibition of 5-lipoxygenase/cyclooxygenase is not simply due to interception of peroxyl radicals generated at the active site of the enzymes. Many of the flavonoids and other compounds (including carnosol, vitamin E and trolox c) stimulated Fe3+/bleomycin-dependent DNA degradation. Those flavonoids which stimulated DNA degradation at low concentrations but which inhibited it at higher concentrations ("biphasic" effect, possibly caused by changing relative contributions of ability to reduce ferric-bleomycin or to chelate iron ions from the bleomycin) were selective inhibitors of 5-lipoxygenase compared to cyclo-oxygenase. In contrast, those flavonoids that did not stimulate DNA degradation at all proved to be cyclo-oxygenase selective inhibitors. Compounds that increased Fe3+/bleomycin-dependent DNA damage up to a maintained plateau were non-selective inhibitors of both 5-lipoxygenase and cyclo-oxygenase. Thus, a combination of iron-chelating and iron ion-reducing properties appears to be required for selective 5-lipoxygenase inhibition by phenolic compounds. Carnosol, vitamin E and trolox c were also found to be 5-lipoxygenase inhibitors of varying potency, and all were less active as cyclo-oxygenase inhibitors.

Abietanes↗

PubMed1991

Status of hepatic heme and heme oxygenase during Plasmodium yoelii nigeriensis infection in mice.

Plasmodium yoelii nigeriensis infection in albino mice caused a significant increase in hepatic heme level, the increase being concomitant with a rise in parasitemia. This elevated heme was found to be associated with all the subcellular fractions except the cytosol, where its content remained unaltered. Activity of heme oxygenase, the key enzyme responsible for catabolism of heme, also increased progressively with rise in parasitemia. Treatment of normal mice with cobalt chloride [60 mg (kg body wt)-1; subcutaneously] brought about a 150% increase in the level of heme oxygenase; similar treatment of infected mice at low parasitemia could induce the enzyme activity while at high parasitemia the enzymic activity remained unaltered as compared to untreated infected mice. In spite of an increased level of heme oxygenase in the cobalt-treated mice, the level of heme did not show any noticeable change. Oral administration of chloroquine [64 mg (kg body wt)-1 x 4 days] brought about a 56% reduction in the level of heme oxygenase of normal animals but there was no change in infected animals when compared with the corresponding untreated infected mice. However, the amount of chloroquine present in livers of normal and infected animals was not significantly different.

Administration, Oral↗

PubMed1993

Inhibition of heme oxygenase after oral vs intraperitoneal administration of chromium porphyrins.

The effects of chromium porphyrins on suckling rat heme oxygenase activity were compared following oral vs intraperitoneal dosing. Chromium protoporphyrin (CrPP), chromium mesoporphyrin (CrMP), or chromium deuteroporphyrin 2,4 bis glycol (CrBG) were administered at 40 mumol/kg to 2-week old suckling rats either orally or intraperitoneally. Six hours after intraperitoneal dosing, CrPP and CrMP had significantly reduced hepatic and splenic heme oxygenase activity by more than 55%. CrBG effectively reduced hepatic heme oxygenase activity by 42%. More importantly, only CrMP was an effective inhibitor of hepatic heme oxygenase activity 6 hr after oral administration. In the first reported comparison of chromium porphyrin efficacy in vivo, our data suggest that chromium porphyrins, and particularly CrMP, may be effective in chemopreventive strategies for the treatment of neonatal jaundice.

Administration, Oral↗

PubMed1994

TOL plasmid-specified xylene oxygenase is a wide substrate range monooxygenase capable of olefin epoxidation.

Xylene oxygenase, which is encoded on the TOL plasmid pWWO of Pseudomonas putida mt-2, is a key enzyme system in the degradation of toluene and xylenes by this organism. It was expressed in an Escherichia coli recombinant strain carrying the xylMA structural genes. This recombinant, which expressed xylene oxygenase from the heat-shock induced lambda PL promoter, was analyzed for its potential as a biocatalytic tool so as to effect the oxidation of side chains of aromatic hydrocarbons to the corresponding alcohols. Compounds that were tested as potential substrates carried different substituents on the aromatic ring at ortho, meta, and para positions, relative to the methyl moiety. Products that accumulated after administration of the aromatic hydrocarbons to concentrated suspensions of the recombinant were identified by gas chromatography and mass spectrometry. Toluene derivatives with ortho substituents could not serve as substrates for the biocatalyst, whereas a number of meta- or para- substituted analogs were efficiently oxidized to the corresponding benzylalcohols. Bioconversion of the substrates by resting cells varied from 3 mumol min-1 g-1 cell dry weight for 1,3,5-trimethylbenzene to 18 mumol min-1 g-1 cell dry weight for meta-xylene. Whole cells that expressed xylene oxygenase did catalyze the oxidation of the methyl substituent attached to a benzene ring, but no conversion of n-alkylbenzene derivatives with longer side chains was observed. Although the ethyl group of ethylbenzene could not be converted by the biocatalyst, cells containing xylene oxygenase were capable of oxidizing the ethylene side group of styrene to produce styrene epoxide.

Alkenes↗

PubMed1995

Differential effects of 3 dipyridyl isomers on hepatic microsomal cytochrome P450 and heme oxygenase in rats.

We compared the effects of 3 dipyridyl isomers, 2,2'-dipyridyl, 2,4'-dipyridyl and 4,4'-dipyridyl, on hepatic microsomal heme oxygenase and drug-metabolizing enzyme activities in male rats. 2,2'-Dipyridyl increased cytochrome P450 (P450) content at lower doses, but decreased with increasing dose levels. Immunoblot analysis revealed that 2,2'-dipyridyl did not induce both P450 1A1/2 and P450 2B1/2, in contrast to 2,4'- and 4,4'-dipyridyls, both of which were inducers of either P450 1A1/2 and/or P450 2B1/2. Some drug-metabolizing enzyme activities gradually declined with the increasing dose level of 2,2'-dipyridyl. 2,2'-Dipyridyl was able to induce hepatic microsomal heme oxygenase in a dose-dependent manner, but 2,4'- and 4,4'-dipyridyls did not, even at the highest dose (0.80 mmol/kg) examined. Treatment of rats with 2,2'-dipyridyl resulted in the increase of glutathione (GSH) content in a dose-dependent manner, but not 4-substituted isomers. A time course study with 2,2'-dipyridyl revealed that it produced a significant decrease in hepatic GSH content at early time periods (2-6 h) after its administration with an inverse increase in heme oxygenase activity. The present investigation has revealed that in contrast to the induction of P450 by 4-substituted dipyridyl compounds, 2,2'-dipyridyl is a novel inducer of hepatic microsomal heme oxygenase, together with the change in hepatic GSH content. This study would provide information on the differential effects of simple dipyridyl isomers on hepatic enzymes involved in heme and drug metabolism.

2,2'-Dipyridyl↗