Biomedical subjects

A Kappas

Publications and source records attributed to A Kappas.

At least 55 records · Page 3Linked to original sources

PubMed1995

Adenovirus-mediated heme oxygenase-1 gene transfer into rabbit ocular tissues.

PURPOSE: Heme oxygenase-1 (HO-1) is a stress protein induced up to 100-fold within a few hours after exposure to oxidative stress, and it has been shown to counteract oxidative injury induced by ultraviolet light or free radicals. The current study was undertaken to determine whether the HO-1 gene can be introduced into adult rabbit ocular tissues by microinjection of a recombinant replication-deficient adenovirus human HO-1 cDNA (Adv-HHO). METHODS: Human HO-1 gene was used for transfection studies to differentiate endogenous from transfected HO. The purified Adv-HHO construct (10(8) pfu/ml) was mixed with lipofectamine and microinjected into the anterior chamber, vitreous cavity, and subretinal space of New Zealand rabbit eyes. After 2 weeks, total RNA was extracted from different ocular tissues, reverse transcription-polymerase chain reaction was performed using specific human HO-1 primers, and amplification products were subjected to Southern hybridization. RESULTS: Transfection with the Adv-HHO construct into rabbit corneal epithelial cells in culture resulted in a functional expression of the human HO-1 gene; the human HO-1 mRNA was detected, and enzyme activity increased threefold. Human HO-1 mRNA was detected in the retina after microinjection of the Adv-HHO construct into the subretinal space. Microinjection into the vitreous resulted in HO-1 mRNA expression in the corneal endothelium, iris, lens, and retina; after intracameral injection of the Adv-HHO construct, human HO-1 mRNA was detected in corneal epithelium and endothelium, ciliary body, lens, and iris. Regardless of the injection site, transfected human HO-1 mRNA was undetectable in tissues outside the eye, that is, brain, liver, and kidney. CONCLUSIONS: These results demonstrated a tissue-selective functional transfer of the human HO-1 gene into rabbit ocular tissues in vivo. This technique may be a promising means for delivering HO-1 gene in vivo as a protective mechanism against oxidative stress that contributes to the pathogenesis of ocular diseases such as cataract, light-induced injury, age-related macular degeneration, and diabetic retinopathy.

Adenoviruses, Human↗

PubMed1995

Direct comparison of Sn-mesoporphyrin, an inhibitor of bilirubin production, and phototherapy in controlling hyperbilirubinemia in term and near-term newborns.

BACKGROUND: Sn-mesoporphyrin (SnMP) is a potent inhibitor of bilirubin production. In our previous studies a single dose (6 mumol/kg birth weight) significantly moderated hyperbilirubinemia and reduced phototherapy (PT) time by > 75% when administered within 24 hours of birth to preterm infants. OBJECTIVE: To directly compare the efficacy of SnMP and PT for controlling hyperbilirubinemia in term and near-term infants. METHODS: Two randomized, sequentially analyzed trials (Study I: male term infants; Study II: infants of both sexes and gestational age [GA] 245-265 days) were conducted. SnMP (6 mumol/kg birth weight) or PT (Phillips F20T12/BB lamps) was administered to paired infants according to strict criteria of plasma bilirubin levels and age. Time of enrollment and closure of cases and crossover, if necessary, of SnMP infants to PT or all infants to exchange transfusion were precisely defined in each pair. SnMP or PT was considered superior if the time between enrollment and closure of the case was reduced by > 24 hours over the alternative treatment or if crossover had occurred. RESULTS: None of the 44 SnMP-treated infants required supplemental PT. Of the 22 pairs of term infants enrolled in Study I, SnMP proved superior to PT in 20 and equal in two. Of the 20 pairs of near-term infants enrolled in Study II, SnMP was superior in 12 and PT in two; six were tied. Two SnMP-treated infants were unpaired. The PT-treated infants in Study I required an average of 33 hours of treatment; those in Study II, 48 hours. None of the enrolled infants required exchange transfusion or interruption of breast-feeding. In both studies, times between case enrollment and closure were reduced by > 30 hours in SnMP compared with PT infants; requirements for additional days of medical observation and bilirubin measurements were also significantly less in SnMP infants. CONCLUSION: A single dose of SnMP entirely supplanted the need for PT in jaundiced term and near-term newborns and significantly reduced medical resource use to monitor hyperbilirubinemia.

Female↗

PubMed1994

Antimutagenicity of three isomers of aminobenzoic acid in Salmonella typhimurium.

The m-, o- and p-isomers of aminobenzoic acid (ABA) repressed the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Salmonella typhimurium TA100. Their antimutagenic potency was in the order of o-ABA > m-ABA > p-ABA. The mechanism of this antimutagenicity is ascribed mainly to the decomposition of MNNG induced by the aminobenzoic acid isomers outside or within the bacterial cells. The inhibition of plant cell peroxidases and bacterial acetyltransferases that are required for the plant activation of 2-aminofluorene (2-AF) to mutagenic product(s) may participate in the repression of 2-AF mutagenesis by the aminobenzoic acids in S. typhimurium strain YG1024. The aminobenzoic acid isomers exhibited no inhibitory effects towards the direct-acting agent 2-acetoxy-2-acetylaminofluorene, the stable diacetylated metabolic product of 2-AF.

Acetoxyacetylaminofluorene↗

PubMed1994

Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene.

Heme oxygenase (HO) is the rate-limiting enzyme in heme catabolism and its activity is induced by many agents, including its substrate heme, heavy metals, UV radiation, and other injurious oxidant conditions. We examined the presence of several regulatory elements in the promoter region of the human HO-1 gene which could possibly account for its induction in response to diverse agents or influences. Heme treatment increased both HO activity and HO-1 mRNA in the human erythroleukemic cell line K562. Electrophoretic mobility-shift assays of nuclear protein extracts from heme-treated and control cells with specific oligonucleotide probes containing binding sites for known transcription factors, including AP-1, AP-2, Sp1, NF-kappa B, CTF/NF1, TFIID, OKT1, and CREB, and oligonucleotides containing serum-, metal-, and glucocorticoid-responsive elements demonstrated a specific and marked increase in the NF-kappa B and AP-2 transcription factors and, to a lesser extent, an increase in AP-1. No significant increase in other transcription factors over the control, untreated cells was observed. DNase I footprint assays using purified transcription factors revealed the presence of NF-kappa B and AP-2 binding sites in the proximal part of the promoter region of the human HO-1 gene. Moreover, nucleotide sequence analysis of the HO-1 promoter region showed that the protected regions encompassed NF-kappa B and AP-2 consensus binding sites. The presence of regulatory sequences for the binding of transcription factors such as NF-kappa B and AP-2, whose activation is associated with the immediate response of the cell to an injury, may be an indication of the important role which HO-1 may play in defense mechanisms against tissue injury.

Animals↗

PubMed1994

Characterization of a 142-bp fragment of the murine c-fos oncogene promoter upstream of the SIF-binding element.

We previously reported that in transformed mouse sarcoma cells of spontaneous origin and in revertants transfected with a fos-cat fusion, the 600-bp c-fos promoter region provides chloramphenicol acetyltransferase activity. In the present study, we investigated the binding of transcriptional factor protein(s) to a region (-503 to -361) upstream of the sis (platelet-derived growth factor)-inducible factor (SIF)-binding element. Gel electrophoresis retardation (GER) assay clearly demonstrated the appearance of strong binding activity to a newly described fragment in the 142-bp region studied. Further analysis using synthetic oligodeoxyribonucleotides and GER defined a binding region of 30 bp (AvaI-AvaII) from -503 to -472 that partially overlaps with a region known to bind fos promoter binding site 2 (FBS2). DNase I footprint analysis discovered a novel sequence in the upstream region of the c-fos promoter to which protein(s) in nuclear extracts from various mouse and human cells bind. This factor(s) is not identical to most known transcriptional factors present in the promoter region of nuclear oncogenes. A proximal part of this fragment is very conservative and contains several AP-2-like-binding sites.

Animals↗

PubMed1994

Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria.

The molecular defect of uroporphyrinogen decarboxylase (UROD) was examined in a patient with mild hepatoerythropoietic porphyria. To elucidate the UROD defect, we cloned UROD cDNAs from EBV-transformed lymphoblastoid cells of the proband using reverse transcriptase-polymerase chain reaction. Nucleotide sequence analysis of the cloned UROD cDNAs revealed two separate missense mutations, each occurring in a separate allele. One mutation was a Val134-->Gln transition, and was due to three sequential point mutations (T417G418T419-->CCA); the other mutation was a His220-->Pro transition (A677-->C). UROD phenotype studies demonstrated that the TGT-->CCA mutation was inherited from the father, and the A-->C mutation was inherited from the mother. In contrast to the null activity previously described for a mutant UROD from a patient with familial porphyria cutanea tarda, these mutant URODs had subnormal but substantial enzyme activities, when expressed in Chinese hamster ovary cells. This is the first demonstration of a mutation caused by three sequential base substitutions.

Adult↗

PubMed1994

Distribution of metalloporphyrin inhibitors of heme oxygenase among serum transport proteins.

Porphyrins are transported in the serum bound to proteins and lipoproteins; the particular component(s) to which a porphyrin is bound influences its distribution in the body. In these experiments, the fractions of serum to which several metalloporphyrin inhibitors of the microsomal enzyme heme oxygenase bind were determined. Sn-mesoporphyrin and Sn-protoporphyin were associated almost entirely with serum albumin and Sn-diiododeuteroporphyrin almost completely with the lipoprotein fraction; Zn-mesoporphyrin was associated with all fractions. Serum transport proteins may be targets of photosensitization by photoactive metalloporphyrins. A decrease in the binding constant of bilirubin to Sn-mesoporphyrin-mediated photosensitized human serum albumin (HSA) was observed following illumination at 50 W/m2 in the spectral range of 520-700 nm; there were 2.0 +/- 0.2 bilirubins bound per HSA for samples illuminated < 120 min; following 180 min illumination, the stoichiometry decreased to 1.5 +/- 0.1 bilirubin per HSA. In a similar experiment with Zn-mesoporphyrin, the porphyrin was fully photooxidized to a nonphotoactive and noninhibiting product after 1 min illumination. The light reaching a porphyrin through human skin would be considerably less than that utilized under these in vitro conditions, and such effects on serum proteins, if demonstrable at all in vivo, would be expected to be far less pronounced than those measured here.

Bilirubin↗

PubMed1994

Incorporation of metalloporphyrin inhibitors of heme oxygenase into micelles and liposomes.

Spectral and photodynamic properties of a porphyrin are sensitive to the environment in which it is localized. By comparison of absorption maxima of porphyrins bound to micelles, proteins or artificial membranes with peak wavelengths in homogeneous solutions of known dielectric constant, the relative polarity of the microenvironment surrounding a porphyrin can be estimated. We have focused our examination on the ability of two synthetic metalloporphyrin inhibitors of heme oxygenase, Sn(IV)-mesoporphyrin (SnMP) and Zn(II)-mesoporphyrin (ZnMP), to partition into charged and uncharged detergent micelles and liposomes. SnMP and ZnMP are intercalated into micelles with cationic surface charges but only ZnMP into nonionic micelles, suggesting that the ionic character of the two anionic axial ligands of SnMP, as well as that of the ionized carboxylic acids of both porphyrins, is a predominant force in the interactions of these compounds. Absorbance shifts of SnMP and ZnMP bound to serum albumin suggest that both porphyrins are localized within an environment with polarity similar to that of ethanol. Spectral changes upon incubation of ZnMP into liposomes (with or without surface charges) indicate that the porphyrin is incorporated into the polar region of the bilayer, i.e. at the border between hydrophilic headgroups and hydrophobic lipids. Illumination of ZnMP within the liposomal membrane resulted in a rapid rate of oxygen uptake, consistent with lipid peroxidation occurring within the bilayer.

Heme Oxygenase (Decyclizing)↗

PubMed1994

Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin.

BACKGROUND: Studies in vitro, in animal models, and in adult and newborn humans have demonstrated that certain tin(Sn)-porphyrins that competitively inhibit the activity of heme oxygenase, the rate-limiting enzyme in heme catabolism, reduce production of bilirubin and can thereby substantially diminish plasma levels of the bile pigment. OBJECTIVES: To assess the effectiveness of increasing doses of the heme oxygenase inhibitor, Sn-mesoporphyrin (SnMP), in moderating the development of significant hyperbilirubinemia and thus the requirements for phototherapy in preterm newborns. METHODS: In five randomized, blinded, placebo-controlled trials, SnMP in increasing doses from 1 mumol to 6 mumol/kg body weight was administered intramuscularly in the first 24 hours of life in preterm newborns of 210 to 251 days gestational age. "Special blue" lamps (Phillips F20T12/BB) were used for phototherapy in newborns exceeding a predetermined plasma bilirubin concentration, irrespective of study group. RESULTS: A total of 517 newborns were randomized in the five trials carried out sequentially over a 4-year period. SnMP in a dose-related manner significantly ameliorated the course of hyperbilirubinemia in the treated newborns of all gestational ages. With a SnMP dose of 6 mumol/kg body weight, the mean peak incremental plasma bilirubin concentration was reduced by 41% and the phototherapy requirements were decreased by 76% compared to control subjects. Erythema observed in a few SnMP-treated newborns who required phototherapy was mild, transient, and without sequelae. No other untoward effects were observed during hospitalization or at a follow-up at post-term age of 3 and 18 months. CONCLUSIONS: SnMP, by inhibiting the production of bilirubin, substantially moderates the development of hyperbilirubinemia in preterm newborns. This compound and similarly acting enzyme inhibitors merit further clinical study as agents for controlling neonatal hyperbilirubinemia, particularly in neonatal populations for whom other treatment modalities are not available.

Bilirubin↗

PubMed1993

Additive effect of erythropoietin and heme on murine hematopoietic recovery after azidothymidine treatment.

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT-treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.

Anemia↗

PubMed1993

The role of inorganic metals and metalloporphyrins in the induction of haem oxygenase and heat-shock protein 70 in human hepatoma cells.

The role of inorganic metals and metalloporphyrins in the induction of mRNAs for haem oxygenase and heat-shock protein 70 (hsp70), the two heat-shock proteins, was examined in human HepG2 and Hep3B hepatoma cells. SnCl2, but not Sn-protoporphyrin, was found to be a potent inducer of both haem oxygenase and hsp70 mRNAs. In contrast, CoCl2, ZnCl2 and FeCl2 caused little induction of haem oxygenase and hsp70 mRNAs, whereas the porphyrin complexes of these metals strongly induced haem oxygenase mRNA, without influencing the level of hsp70 mRNA. The induction process was largely transcriptional, as judged by the inhibition of induction by actinomycin D, but not by cycloheximide, and by increased transcription demonstrated by nuclear run-off analysis. Since CoCl2 is a potent inducer of haem oxygenase in vivo in animals, the possibility of the biosynthesis of Co-protoporphyrin was examined in human hepatoma cells by incubating them with CoCl2 and protoporphyrin, or delta-aminolaevulinate (ALA), the precursor of protoporphyrin. Both types of treatment led to a potent induction of haem oxygenase mRNA. Co-protoporphyrin formation was also spectrally demonstrated in cells incubated with the metal and ALA. The results of this study indicate that certain metals, e.g. SnCl2, may directly induce haem oxygenase mRNA, whereas with other elements, incorporation of the metal into the porphyrin macrocycle is necessary for induction. Therefore CoCl2, like haemin, may activate the haem oxygenase gene via a haem-responsive transcription factor, whereas SnCl2 may exert its effect via a metal-responsive transcription factor.

Carcinoma, Hepatocellular↗

PubMed1993

Elevated levels of heme oxygenase-1 activity and mRNA in peripheral blood adherent cells of acquired immunodeficiency syndrome patients.

Patients with the acquired immunodeficiency syndrome (AIDS) commonly develop hematological abnormalities, including anemia, leukopenia, and thrombocytopenia. Heme synthesis and heme degradation are critical to the maintenance of cellular heme homeostasis and to hematopoietic differentiation. We examined heme oxygenase activity and expression of the heme oxygenase gene in adherent cells (monocytes-macrophages) obtained from the peripheral blood of AIDS patients and normal controls. Heme oxygenase activity in normal control cells was 43 +/- 16 pmol bilirubin formed/4 x 10(5) cells/hr as compared to 133 +/- 30 pmol bilirubin formed/4 x 10(5) cells/hr in the AIDS patients. Via blot hybridization analysis with human heme oxygenase cDNA, heme oxygenase mRNA levels in cells of the normal and the AIDS patients were compared. Total RNA from normal cells displayed only weak hybridization with the cDNA probe. In contrast, cells from peripheral blood of the AIDS patients displayed marked increases over normal levels in heme oxygenase mRNA. Heme oxygenase activity could be substantially suppressed by the competitive inhibitor of the enzyme, Sn-mesoporphyrin. Elevated heme oxygenase activity in cells of AIDS patients could produce a decrease in cellular heme needed for transductional signalling for the growth factor network, which regulates the hematopoietic microenvironment, and for other metabolic purposes. Suppression of heme catabolism by inhibitors of this enzyme may thus be useful in potentiating erythropoietic responses in this disorder.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Synergistic effect of heme and IL-1 on hematopoietic stromal regeneration after radiation.

Results from this study show that a combination of heme and interleukin-1 (IL-1) treatment resulted in the most improved recovery of hematopoietic-stromal regeneration after sublethal irradiation. Less pronounced effects were obtained when heme or IL-1 were given singly. Sublethal irradiation of mice produced an initial (as early as day 1) intense depression of the hematopoietic system as evidenced by leukopenia. In vivo treatment of animals with heme in combination with IL-1, accelerated hematopoietic and stromal regeneration as determined by hematopoietic spleen colony forming unit assay (CFU-S), erythroid (BFU-E), myeloid (CFU-GM) clonal cultures, long-term bone marrow cultures (LTBMC), and the ability to regenerate hematopoiesis by ectopic (renal) stromal hemopoietic transplantation. Sixteen days after irradiation, leukocyte levels in heme and IL-1 treatment groups were higher than non-treated animals and were near normal values by 27 days. One day after irradiation, the capacity of stromal progenitors to form new bone and hematopoietic cells (ectopic foci) was severely impaired, but recovered after 2-4 weeks. This recovery process was accelerated in heme and IL-1-treated animals. BFU-E, CFU-GM, and CFU-S capacity was also severely impaired in all animals 1-27 days after irradiation. CFU-S was only 0.15% of control by day 1 and 5% of control by day 16. Treatment with heme or IL-1 improved recovery by as much as 70% after 27 days of irradiation. A similar but enhanced recovery was seen for BFU-E and CFU-GM, with erythroid recovery the best. Total cellularity, adherent cell layer (ACL) formation, and clonogenic capacity by LTBMCs (10 weeks) derived from irradiated animals was severely reduced, whereas the hematopoietic capacity by LTBMCs derived from heme- and IL-1-treated animals had recovery values similar to non-irradiated controls. These results suggest therapeutic use of heme and IL-1 after chemotherapy or bone marrow depression may be beneficial.

Animals↗

PubMed1993

Comparative study on the mutagenicity of three structurally related substituted aniline mustards in the Salmonella/microsome assay.

The ortho, meta and para isomers of N,N-bis(2-chloroethyl)aminocinnamic acid were tested for their ability to mutate Salmonella typhimurium strains in the Salmonella/microsome mutagenicity test. The aim of the work was to establish a structure-activity relationship between these three isomers. The drugs were found to induce base-pair substitutions, causing dose-dependent increases in his+ revertants, in strains TA100 and TA1535. The study showed that the position of the substituent groups influenced the mutagenic activity of the compounds. The ortho isomer exhibited a poorer mutagenic effect than meta and this was found to be a weaker mutagen than para. The presence of metabolic activation enzymes in the test system induced a further increase in his+ revertants, in strains TA100 and TA1535, which is consistent with the findings for melphalan, a cancer chemotherapeutic agent with a chemical structure similar to that of the isomers tested.

Aniline Mustard↗

PubMed1993

Mutagenicity of four homo-aza-steroidal esters of m-N,N-bis(2-chloroethyl)aminocinnamic acid in the Ames test.

Four new chemicals, the homo-aza-steroidal esters of m-N,N-bis(2-chloroethyl)aminocinnamic acid, originaly synthesized to be used as antineoplastic agents, were tested for their mutagenic activity in the Ames test. 3 beta-Hydroxy-13 alpha-amino-13,17-seco-5-androsten-17-oic-13,17- lactam ester (ACALE3) and 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam ester of m-N,N-bis(2-chloroethyl)aminocinnamic acid (ACALE4) were found to induce base-pair substitutions, causing dose-dependent increases in his+ revertants in strains TA100 and TA1535, while no dose-dependent relations were established when 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam ester (ACALE1) and 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one ester of m-N,N-bis(2-chloroethyl)aminocinnamic acid (ACALE2) were tested. The presence of metabolic activation enzymes in the test system had no effect in his+ revertants in strains TA100 and TA1535. The chemicals tested although having the same alkylating moiety and a similar chemical structure exhibited different mutagenic activities.

Androstanes↗

PubMed1993

Targeted delivery of a heme oxygenase inhibitor with a lyophilized liposomal tin mesoporphyrin formulation.

Tin mesoporphyrin (SnMP) is a competitive inhibitor of heme oxygenase being examined clinically for the treatment of hyperbilirubinemia. Since liposomes have been shown to target SnMP to the spleen and increase its efficacy (S. A. Landaw, G. S. Drummond, and A. Kappas, Pediatrics 84, 1091-1096, 1989), we began investigating the feasibility of the preparation and scaleup of a liposomal SnMP formulation for clinical use. SnMP liposomes were prepared by high-pressure homogenization of a suspension of SnMP and egg phosphatidylcholine (1:20, w/w) in lactose-phosphate buffer, resulting in SnMP liposomes that were less than 200 nm in diameter and had encapsulation efficiencies of up to 90% at pH 5. The SnMP liposomes could be sterile filtered and lyophilized in a 1-day cycle with retention of the encapsulation efficiency and particle size. Following injection into rats, the distribution of liposomal SnMP to spleen at 2 and 6 hr after dosing was 5-20 times higher than for aqueous SnMP. Lyophilized SnMP liposomes were also more effective than aqueous SnMP in decreasing bilirubin production in bile-cannulated rats. The results suggest the potential for producing a safe, sterile, and effective lyophilized formulation of SnMP liposomes for targeting of heme oxygenase inhibitors to the spleen.

Animals↗

PubMed1993

Mutagenic activity of the antitumour agent homo-aza-steroidal ester of p-N,N-bis(2-chloroethyl)aminophenoxyacetic acid (NSC 294859) in the Salmonella/microsome assay.

The mutagenic activity of the new antitumour agent 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam- p-N,N-bis(2-chloroethyl)aminophenoxyacetate (NSC 294859) was studied in the Salmonella/microsome assay. It was found to induce base pair substitutions, causing dose-dependent increases in his+ revertants in strains TA100 and TA1535. The alkylating moiety, p-N,N-bis(2-chloroethyl)-aminophenoxyacetic acid, was shown to be less effective than the parent compound, while the modified steroid moiety, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam, showed no mutagenic effect in all strains used. The presence of metabolic activation enzymes in the test system induced a further increase in his+ revertants in strains TA100 and TA1535, in both the parent compound and the alkylating moiety of the parent compound, while it had no effect in the case of the steroidal lactam.

Androstanes↗

PubMed1993

Tin-mesoporphyrin inhibits heme oxygenase activity and heme-iron absorption in the intestine.

Long-term treatment with the heme oxygenase inhibitor tin-mesoporphyrin produces an iron deficiency anemia in rats analogous to that we reported in patients with the Crigler-Najjar type I syndrome receiving prolonged treatment with the inhibitor to ameliorate severe jaundice [Pediatrics 1992; 89: 175-182]. A dose- and time-dependent inhibition of intestinal heme oxygenase is produced by tin-mesoporphyrin which is independent of iron status of the animal. Tin-mesoporphyrin inhibits the intestinal enzyme whether administered orally or parenterally. Enzyme inhibition by either route results in diminished uptake of 59Fe from radiolabelled heme in the gut. Since tin-mesoporphyrin stimulates excretion of unmetabolized heme into bile its ability to inhibit intestinal heme oxygenase and to decrease heme-iron absorption in the gut probably accounts in part for the iron deficiency produced by the agent. The availability of an orally active agent which inhibits heme oxygenase and heme-iron absorption in the intestine may prove useful for experimental and therapeutic studies in diseases of iron metabolism.

Anemia, Hypochromic↗