Cytochrome P-450 Mixed Function Oxidase Research Articles

Effect of protein and calorie restriction on the cytochrome P-450 isozyme (P-450 IID6) activity in rats

Dextromethorphan (DXM) is commonly used as probe for the metabolic activity of the debrisoquine isozyme (P-450 IID6) of the cytochrome P-450 mixed-function oxidase system. Several reports have described changes in P-450 activity with dietary alteration. This study was conducted to determine the effect of protein and calorie restriction on DXM metabolism in Sprague Dawley (SD) rats. Four- to five-week-old male SD rats were fed one of four dietary regimens: a regular diet containing 22.5% protein ad libitum (REGLIB); a low protein (8%) diet fed ad libitum (PROLIB); a regular protein diet, but only 50% by weight of that consumed by the REGLIB group (REG50); a low protein (8%) diet, but only 50% by weight of that consumed by the PROLIB group (PRO50). The DXM log m molar metabolic ratio (LMR) calculated as the ratio of the urinary DXM to its metabolite dextrorphan concentration was measured at the beginning of the study and after 5 weeks of feeding. Groups REG50, PROLIB, and PRO50 received 49%, 57%, and 29% of the calorie intake and 49%, 24%, and 12% of the protein intake of group REGLIB, respectively. Their weight gain was 24%, 40%, and 3% of that gained by REGLIB. LMR significantly decreased for REGLIB and PROLIB indicating an increase in DXM metabolism. The LMR of REG50 and PRO50 did not change. DXM metabolism continues to develop in these rats during the first 7 to 8 weeks of life. Energy restriction inhibited the maturation of DXM metabolism, while protein restriction did not significantly affect DXM metabolism.

Effects of arsenite on hepatic mixed-function oxidase activity in rats.

1. Injection of arsenite (As3+) to control rats results in losses of total hepatic cytochrome P-450 and significant decreases of ethoxycoumarin O-deethylase (ECOD) and ethoxyresorufin O-deethylase (EROD) activities. However, As3+ appears to decrease the activity of these enzymes differentially, with EROD showing greater sensitivity than ECOD. 2. Injection of As3+ to rats treated with phenobarbital and isosafrole significantly decreases the total content of hepatic cytochrome P-450 and various mixed function oxidase (MFO) activities, with the exception of ECOD which appears to be insensitive to As3+. 3. 3-Methylcholanthrene administration apparently protects against the effects of As3+ on the cytochrome P-450 system, since total content of the cytochrome P-450 and various MFO activities were all insensitive to this treatment.

Nomenclature for hydrocarbon-inducible cytochrome P450 in fish

A growing number of studies concerning organic chemical pollutant induction of cytochrome P450 mixed function oxidases in fish stimulate a need for common terminology. Similar names for proteins might be based on similarities in function, in regulation, and in their structure. Under the current guidelines for P450 proteins, classification is based on measured or inferred amino acid sequence. At present, a single teleost hydrocarbon-inducible P450 (rainbow trout) can conclusively be termed 1A1: a second (scup P450E) can be so termed on the basis of partial sequence. The lack of primary sequence information makes it difficult to assign a specific identity to hydrocarbon inducible P450s in other fish. Nevertheless, the sum of information on catalytic activities, introduction and immunological cross-reactivities provides a weight of evidence sufficient to assume (but not prove) gene family (I) and subfamily (A) identities for hydrocarbon-inducible proteins in many species. Reference to these proteins as P4501 or IA (or CYPI or IA) in fish species where sequence data are lacking is suggested as more appropriate than reference to them as P450IAI (or CYPIAI). Additional primary sequence data are required to further define orthologous relationships among P450IA genes in fish, and to determine whether IAI is a correct designation for a hydrocarbon-inducible P450 in many species.

Differential effects of proteinase K on the components of the liver microsomal cytochrome P-450 mixed function oxidase system.

Differential effects of proteinase K on the components of the liver microsomal cytochrome P-450 mixed function oxidase system.

Comparative in vitro metabolism of the cannabinoids

The metabolism of delta-9-tetrahydrocannabinol (delta-9-THC), delta-8-THC, delta-11-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG) and the equatorial-isomer of hexahydrocannabinol (HHC) was studied in microsomal preparations obtained from rats, mice, guinea pigs, rabbits, hamsters, gerbils and a cat. Identification of metabolites was by GC/MS and quantification by gas chromatography. Major metabolites were monohydroxylated compounds but the pattern of hydroxylation varied considerably between the species, no doubt reflecting the variable nature of the cytochrome P-450 mixed-function oxidases. Although the primary carbon allylic to the endocyclic double bond of tricyclic cannabinoids was usually the major site of attack, the 4′ (side-chain, omega-1 position) and the terpene ring were usually favoured by the cat and hamster respectively. The guinea pig generally produced more metabolites hydroxylated in the side-chain (all positions) than did the other species. The results from HHC were very similar to those from THC, namely hydroxylation at C-11 in most species, and the production of high concentrations of 8alpha-hydroxy-HHC in the mouse and 8beta-hydroxy-HHC in the hamster. As this molecule lacks the double bond of the THCs and, hence, the allylic nature of C-11 and C-8, the results suggest that it is the orientation of the molecule to the active site of the cytochrome P-450 mixed-function oxidase rather than the reactivity of the CH bond that governs the position of hydroxylation.

Ifosfamide/Mesna

Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Mesna, a uroprotective thiol agent, is routinely administered concomitantly with ifosfamide, and has almost eliminated ifosfamide-induced haemorrhagic cystitis and has reduced nephron toxicity. Therapeutic studies, mostly noncomparative in nature, have demonstrated the efficacy of ifosfamide/mesna alone, or more commonly as a component of combination regimens, in a variety of cancers. In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, a salvage regimen of ifosfamide/mesna, cisplatin and either etoposide or vinblastine produced complete response in approximately one-quarter of patients. As a component of both induction and salvage chemotherapeutic regimens, ifosfamide/mesna has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin's and Hodgkin's lymphoma, and ovarian cancer. Induction therapy with ifosfamide/mesna-containing chemotherapeutic regimens has been encouraging in non-small cell lung cancer, adult soft-tissue sarcomas, and as neoadjuvant therapy in advanced cervical cancer. As salvage therapy, ifosfamide/mesna-containing combinations have a palliative role in advanced breast cancer and advanced cervical cancer. Ifosfamide/mesna can elicit responses in patients refractory to numerous other antineoplastic drugs, including cyclophosphamide. With administration of concomitant mesna to protect against ifosfamide-induced urotoxicity, the principal dose-limiting toxicity of ifosfamide is myelosuppression; leucopenia is generally more severe than thrombocytopenia. Reversible CNS adverse effects ranging from mild somnolence and confusion to severe encephalopathy and coma can occur in approximately 10 to 20% of patients after intravenous infusion, and the incidence of neurotoxicity may be increased to 50% after oral administration because of differences in the preferential route of metabolism between the 2 routes of administration. Other adverse effects of ifosfamide include nephrotoxicity, alopecia, and nausea/vomiting. In general, intravenously administered mesna is associated with a low incidence of adverse effects; however, gastrointestinal disturbances are common following oral administration. Thus, ifosfamide/mesna is an important and worthwhile addition to the currently available range of chemotherapeutic agents. It has a broad spectrum of antineoplastic activity and causes less marked myelosuppression than many other cytotoxic agents. At present, the role of ifosfamide/mesna in refractory germ cell testicular cancer is clearly defined; however, its overall place in the treatment of other forms of cancer awaits delineation in future well-controlled comparative studies.

Effects of the immunosuppressant FK-506 and its analog FK-520 on hepatic and renal cytochrome P450 mixed-function oxidase

The novel immunosuppressant FK-506 and its analog FK-520 were found to inhibit the hepatic microsomal mixed-function oxidase system in male Sprague-Dawley rats. At 5 and 10mg/kg/ day, s.c., for 6 days they caused 30–80% decreases in cytochrome P450 levels, NADPH-cytochrome P450 reductase, and benzphetamine N-demethylase activities. The metabolism of FK-506 itself was inhibited by 50%. FK-506 and FK-520 had a minimal effect on the renal cytochrome P450 levels unlike cyclosporin A which produced a 67% increase after six daily 25 mg/kg doses. A single dose of FK-506 (25 mg/kg, s.c.) had a minimal effect on the hepatic or renal metabolizing enzyme system. In vitro, addition of FK-506 and FK-520 to human and control rat liver microsomes resulted in a concentration-dependent inhibition of benzphetamine N-demethylation (10–20% at 50 μM, 60–75% at 250 μM). We suggest that in view of its potential to inhibit hepatic cytochrome P450-dependent mixed-function oxidase, resulting in the inhibition of its own metabolism, FK-506 should be administered with caution to transplant patients.

The hydrophobic amino-terminal sequence of bovine 17 alpha-hydroxylase is required for the expression of a functional hemoprotein in COS 1 cells.

The endoplasmic reticulum is a major site of localization for eukaryotic cytochrome P-450 mixed-function oxidase complexes. Previous studies have shown that the microsomal forms of P-450 insert into the membrane via their hydrophobic amino terminus through the signal recognition particle-dependent pathway. We have examined the insertion of bovine 17 alpha-hydroxylase (P45017 alpha) into the endoplasmic reticulum of COS 1 cells to evaluate the functional role of its hydrophobic amino-terminal sequence and membrane insertion. An NH2-terminal truncated protein, P450 delta 2-17, which lacked amino acids 2-17 was expressed in COS 1 cells, subcellular fractions were isolated, and P450 delta 2-17 was localized by immunoblot analysis. Compared to the full-length P45017 alpha, the NH2-terminal truncation resulted in a 2.5-fold decrease in P45017 alpha protein recovered with the microsomal fraction, 50% of which was an integral membrane protein as defined by resistance to Na2CO3 extraction. Despite correct membrane localization, P450 delta 2-17 was not a functional enzyme in COS 1 cells. A CO difference spectrum of microsomes containing P450 delta 2-17 did not give a typical 450 nm absorbance. We conclude that the hydrophobic amino terminus is required for the expression of a functionally competent P45017 alpha in COS 1 cells and suggest that the insertion of the amino terminus into the membrane is necessary for the folding of this protein into its correct structural form.

Critical Ketoconazole Dosage Range for Ciclosporin Clearance Inhibition in the Dog

Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p greater than 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p greater than 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p less than 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p greater than 0.05). We conclude from these new observations that the KC-induced decrease in CsA Cl(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5-10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.

Rapid publication: Constitutive expression of a vitamin D 1-hydroxylase in a myelomonocytic cell line: A model for studying 1,25-dihydroxyvitamin D production in vitro

The capacity of the v-myc-transformed, chicken myelomonocytic cell line HD-11 to metabolize 25-hydroxyvitamin D3 (25-OHD3) was examined. HD-11 cells produced and secreted a metabolite of 25-OHD3 that was bound with high affinity by receptor for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. On normal-phase HPLC, this metabolite cochromatographed with authentic 1,25-(OH)2D3 in both hexane- and methylene chloride-based solvent systems. The 25-OHD3 1-hydroxylation reaction was substrate saturable with a Km of 73 nM 25-OHD3 and a maximal velocity of 167 fmol per 10(6) cells per h. This reaction was inhibited by ketoconazole, a recognized inhibitor of cytochrome P450 mixed-function oxidases including the authentic, renal 25-OHD3 1-hydroxylase. On the other hand, HD-11 cell 1,25-(OH)2D3 production was not affected by the antioxidant DPPD, a known inhibitor of free radical-generated 1,25-(OH)2D3. In addition to synthesizing 1,25-(OH)2D3, this monocyte-macrophage cell line also has the potential to be a target for the hormone; HD-11 cells express high-affinity receptor for 1,25-(OH)2D3 (Kin = 0.06 nM).

Influence of cytochrome P450 mixed-function oxidase induction on the acute toxicity to rainbow trout ( Salmo gairdneri) of primary aromatic amines

The influence of enzyme induction on the acute toxicity of aniline and 4-chloroaniline to rainbow trout ( Salmo gairdneri) was investigated. For these two xenobiotics, bioactivation reactions are known to occur in mammals. Induction of cytochrome P450 mixed-function oxidase was obtained by intraperitoneal (ip) injection of trout with a mixture of polychlorinated biphenyls (Aroclor 1254). Five days after ip injection with three different doses of Aroclor 1254 (50, 100, and 200 mg/kg), benzo[ a]pyrene hydroxylase activity in trout liver microsomes increased five- to sixfold. Cytochrome P450 concentrations in the microsomes were slightly, but significantly, enhanced in two of the three dose levels. The 96-hr LC 50's of aniline and 4-chloroaniline were not affected by pretreatment with Aroclor 1254, suggesting that metabolic activation does not necessarily play a role in the acute toxicity of aromatic amines to fish.

Variations in the resistance of Stellaria media to mecoprop due to biotype, application method and 1‐aminobenzotriazole

Summary:An investigation was made into the resistance of some biotypes of Stellaria media to mecoprop. Comparison of the sensitivity of five biotypes to foliar applications of mecoprop salt confirmed the presence of resistant and sensitive types and one of intermediate sensitivity. Applications of mecoprop through the roots of plants growing in nutrient culture were also more active on biotypes sensitive to foliar mecoprop, although the differences were less marked than they were with foliar treatments. Thus, possible differ ences in retention, uptake and translocation do not seem to be important causes of resistance. Consequently, it appears that resistance is associated with detoxification of mecoprop at the site of action. In two further experiments the cytochrome P450 mixed function oxidase inhibitor, 1‐aminobenzotdazole, had only a small effect on the susceptibility of resistant S. media plants to mecoprop. The importance of these data in the elucidation of the mechanism of resistance is discussed.

Comparison of the Parenteral Histamine2-Receptor Antagonists

The chemical structure, pharmacokinetic properties, and drug-drug interaction profiles of the parenterally available histamine2 (H2)-receptor antagonists were compared. Famotidine is a guanidinothiazole derivative, ranitidine contains an aminomethylfuran ring, and cimetidine has an imidazole ring. Data from the literature indicate that because of its chemical structure famotidine has a much greater potency and affinity for the H2-receptor and a notable lack of drug-drug interactions when compared with ranitidine and cimetidine. As a result, famotidine should be considered the H2-receptor antagonist of choice for critically ill patients who require gastric-acid suppression and at the same time are being treated with other drugs that depend on the cytochrome P-450 mixed-function oxidase system for their metabolism and/or on renal tubular mechanisms for their excretion.

Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rat, Syrian hamster, guinea pig, and marmoset

Nafenopin was administered orally for 21 days to male Sprague-Dawley rats (0.5–50 mg/kg/day), Syrian hamsters (5–250 mg/kg/day), Dunkin-Hartley guinea pigs (50 and 250 mg/kg/day), and marmosets ( Callithrix jacchus, 50 and 250 mg/kg/day). With the rat, and to a lesser extent in the hamster, nafenopin treatment produced dose-related increases in liver size and induction of peroxisomal (palmitoyl-CoA oxidation) and microsomal (lauric acid 12-hydroxylase) fatty acid oxidizing enzyme activities. In contrast, in the guinea pig and marmoset, there was no effect on liver size and only comparatively small changes were observed in these enzyme activities. Ultrastructural examination of liver sections from nafenopin-treated rats and hamsters revealed increased numbers of peroxisomes many of which lacked the characteristic crystalline nucleoid. While nafenopin had little effect on peroxisome numbers in either the guinea pig or marmoset, increases in microsomal cytochrome P450 content and mixed function oxidase activities were observed in these species. These results demonstrate marked species differences in nafenopin-induced hepatic peroxisome proliferation with the Syrian hamster being less responsive than the rat and the guinea pig and marmoset being only weakly responsive. As nafenopin is a known hepatocarcinogen in the rat, comparative long-term studies in poorly responsive species, such as the guinea pig and marmoset, may help clarify the role of organelle proliferation in the hepatocarcinogenicity of certain peroxisome proliferators.

Diethylthiocarbamic acid methyl ester: A potent inhibitor of aldehyde dehydrogenase found in rats treated with disulfiram or diethyldithiocarbamic acid methyl ester

Rats were treated with disulfiram (Antabuse®, DSF) or its metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) and challenged with ethanol. The blood pressure response to ethanol was followed and blood was analyzed for DSF, Me-DDC and diethyldithiocarbamic acid (DDC). The rat liver aldehyde dehydrogenase (ALDH) isozyme activities were measured 2 hr after the ethanol challenge. Both treatments produced a significant fall in the blood pressure when challenged with ethanol, probably caused by a marked decrease in hepatocyte low K m and high K m activities. The mean plasma concentration ranges of Me-DDC and DDC were found to be 49–1241 nmol/1 and 182–841 nmol/1, respectively, whereas DSF was undetectable. In addition, it was found that inactivation of hepatocyte low K m ALDH activity was dependent on preoxidation of Me-DDC by the microsomal cytochrome P-450 mixed function oxidases. Me-DDC was found to be oxidized under aerobic conditions in the presence of NADP to form diethylthiocarbamic acid methyl ester (Me-DTC). The structure was confirmed from its MS/EI fragmentation spectrum. Me-DTC was found to be a potent inhibitor of low K m ALDH when added to rat liver homogenate. The compound was also identified as a metabolite in rat blood collected from the DSF and Me-DDC treated rats, and in blood from human alcoholics on DSF treatment. Me-DTC appears to be more selective for the low K m isozymes whereas the opposite seems to be the case for the hydrolytic product, DTC.

Chlorophenoxyacid herbicides induce microsomal cytochrome P-450 IVA1 ( P-452) in rat liver

Induction of the cytochrome P-450 mixed-function oxidase and specifically the cytochrome P-450 IVA1 isoenzyme by seven phenoxyacid herbicides in rat liver have been studied. Liver microsomes from rats orally treated with the herbicides at 3 dose levels showed a significant increase in total cytochrome P-450 content with 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) being the most potent inducer. Benzphetamine N-demethylation, as a marker of cytochrome P-450 b ( P-450 IIB1) activity, was not affected by any of the herbicides studied, whereas cytochrome P-450 c ( P-450 IA1), as assayed by ethoxyresorufin- O-deethylation activity, was significantly increased (up to 2.2-fold) by some of the herbicides. The 12-hydroxylation of lauric acid was significantly induced (3–8-fold) by all seven herbicides, 4-chlorophenoxyacetic acid (CPA) and 2,4,5-trichlorophenoxypropionic acid (2,4,5-TP) being the weakest and most potent inducers respectively. This increase in lauric acid 12-hydroxylase activity was accompanied by an increase in the hepatic content of cytochrome P-450 IVA1 as assessed by both a qualitative Western blot procedure and a quantitative ELISA method. By comparison, lauric acid 11-hydroxylase activity was not or only marginally increased by phenoxyacid herbicide pretreatment. Our results suggest that the phenoxyacid herbicides act as mixed inducers of the cytochrome P-450 mixed function oxidase system, preferentially inducing the cytochrome P-450 IVA1 isoenzyme.

Metabolism of arylhydrazines by cytochrome P-450 mixed function oxidases and prostaglandin(H)synthase from mouse lungs

The arylhydrazines 4-methylphenylhydrazine hydrochloride, N′-acetyl-4-methylphenylhydrazine and N′-acetyl-4-hydroxymethylphenylhydrazine (HMPH) were metabolized by ram seminal vesicle prostaglandin(H)synthase (P(H)S) and by cytochrome P-450- and P(H)S-dependent enzymes from mouse lung. Based on the K m -values, the cytochrome P-450 enzymes were the most efficient, suggesting that they would be responsible for the metabolic activation of these compounds in vivo. Cytochrome P-450-dependent metabolism was inhibited by metyrapone and SKF-525A, ruling out the involvement of flavin mono-oxygenase. Agaritine, an arylhydrazide, was poorly metabolized by both systems.

EXACERBATION OF CYCLOSPORINE TOXICITY BY CONCOMITANT ADMINISTRATION OF ERYTHROMYCIN

Cyclosporine (CsA), an immunosuppressive drug widely used in clinical organ transplantation, causes a variety of side effects, including parenchymal complications of nephrotoxicity and hepatotoxicity. Erythromycin ethinylsuccinate (EES), a macrolide antibiotic frequently administered to transplant patients afflicted with pneumonias caused by Mycoplasma pneumoniae and Legionella pneumophila, markedly potentiated parenchymal drug toxicity in nine (three renal and six cardiac) CsA-treated allograft recipients. The mean and median blood urea nitrogen (BUN), creatinine, and total bilirubin increased upon initiation of EES treatment: in the renal recipients from 27, 1.7, and 0.5 mg/dl, respectively, before, to a mean and median of 81/101, 8.3/3.9, and 2.1/1.2 mg/dl during, and to 72/22, 1.9/1.7, and 0.6/0.5 mg/dl after cessation of EES treatment. The median serum radioimmunoassay (RIA)-determined CsA trough value of 147 ng/ml prior, rose to a zenith of 1125 ng/ml during, EES therapy. In the six cardiac recipients, the mean and median BUN, creatinine, and total bilirubin of 51/45, 1.5/1.3, 1.2/1.3 mg/dl, respectively, before, rose to 100/91, 3.7/3.6, and 2.3/2.1 mg/dl during, and fell to 49/44, 1.8/2.1, and 1.0/0.8 mg/dl after, cessation of EES. The mean serum CsA trough value of 185 ng/ml rose to 815 ng/ml during EES administration. Since EES and CsA are both metabolized by the hepatic cytochrome P450 mixed-function oxidase system, simultaneous use of these two drugs may decrease CsA metabolism, with consequent elevation of blood levels and induction of CsA toxicity. Therefore, blood level monitoring and careful regulation of CsA dose are necessary, in order to achieve the safe use of EES in transplant recipients.

Identification of heme oxygenase and cytochrome P-450 in the rabbit heart

The regulation of cardiac heme oxygenase and cytochrome P-450 mixed function oxidase was studied in the rabbit heart. Heme oxygenase activity is found in ventricular and atrial microsomal fractions. This activity is NADPH dependent, and is inhibited by tin and zinc protoporphyrin, but not by either SKF 525A or 7,8-benzoflavone. Immunologic studies of cardiac heme oxygenase demonstrate that antibodies prepared against human purified hepatic heme oxygenase recognize rabbit atrial heme oxygenase and inhibit the enzyme activity by 92%. In contrast, control immunoglobulin does not inhibit heme oxygenase activity. Further, the western blotting technique demonstrates that a similar band of protein with a molecular weight of 32,000 exists in cardiac microsomes and that no protein cross-reacts with purified hepatocyte heme oxygenase. Marked induction of atrial heme oxygenase is observed in microsomal fractions prepared from rabbits treated with cobalt chloride. Atrial microsomes possess 0.24 nmol of cytochrome P-450 as compared to 0.68 nmol/mg protein in microsomes from the liver. The levels of aryl hydrocarbon hydroxylase (AHH) activity, a cytochrome P-450-dependent enzyme, in ventricle and atrium are stimulated by a NADPH-generating system and are sensitive to 7,8-benzoflavone, and SKF 525A, known inhibitors of cytochrome P-450 mixed function oxidase. AHH activity in ventricular and atrial microsomes is 2-3% of that seen in liver microsomes whereas the P-450 content/mg protein is about 20% of that observed in the liver. AHH activity is mediated by a form of cytochrome P-450 that is inducible by 3-methylcholanthrene/beta-naphthoflavone. A possible new role of the heart cytochrome P-450 system in cardiac function is proposed.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of heme metabolism during the induction of hepatic and renal cytochrome P-450 levels and drug-metabolizing enzymes in rats by a Prudhoe Bay crude oil.

Administration of Prudhoe Bay crude oil (PBCO) to rats resulted in a dose-related increase in liver weight; rapid and marked increase in the activity of hepatic delta-aminolevulinate synthetase, the initial and rate-limiting enzyme in the heme biosynthetic pathway; rapid decline in the activity of hepatic heme oxygenase, the rate-limiting enzyme of heme catabolism; and more gradual increase in the levels of hepatic cytochrome P-450 and some mixed-function oxidase activities such as benzo[a]pyrene hydroxylase and 7-ethoxyresorufin-O-deethylase. PBCO treatment also increased renal cytochrome P-450 levels and mixed-function oxidase activities; however, delta-aminolevulinate synthetase and heme oxygenase activities were unchanged. This suggests that different regulatory mechanism(s) may be involved in renal heme metabolism and induction of monoxygenase system.