127 research outputs found
Patients with delayed-onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins (vol 282, pg 1064, 1997)
No full textPT: J; CR: CRIBB AE, 1997, J PHARMACOL EXP THER, V282, P1064; NR: 1; TC: 1; J9: J PHARMACOL EXP THER; PG: 1; GA: YQ672Source type: Electronic(1
The Homespun Wisdom of Myrtle T. Cribb
No full textThe #1 New York Times bestselling author Sheri Reynolds returns with a “nontraditional devotional”—at once a hilarious and inspirational novel packed with profound advice from the journey of the unforgettable Myrtle Cribb. [Amazon.com]https://digitalcommons.odu.edu/mfa_books/1027/thumbnail.jp
Further investigations of the role of acetylation in sulphonamide hypersensitivity reactions
No full textSulphonamide hypersensitivity reactions are believed to be mediated through reactive intermediates derived from oxidation of the para-amino group to form sulphonamide hydroxylamines. Sulphamethoxazole hydroxylamine (SMX-HA) can be acetylated by N-acetyltransferase (NAT) enzymes to form an acetoxy metabolite (acetoxySMX). In the current studies, acetoxySMX was found to be not toxic over the concentration range of 0 to 500 mu M towards a human lymphoblastoid cell line (RPMI 1788) or a human hepatoma cell line (HepG2). Further, transient expression of NAT1 in COS-1 cells or stable transfection of NAT1 and NAT2 in HepG2 cells did not alter the toxicity of SMX-HA in vitro. The activity of NAT1 in isolated mononuclear leucocytes (a reflection of systemic NAT1 activity) determined with para-aminobenzoic acid as a substrate was not different between controls (n = 11) or patients with a known hypersensitivity reaction (n = 5) (4.1 +/- 1.2 nmol min(-1) mg(-1) vs 5.7 +/- 1.4 nmol min(-1) mg(-1)). Thus, acetoxySMX is unlikely to play a significant role in mediating SMX hypersensitivity reactions and a constitutive deficiency in NAT1 activity is not a common finding in patients susceptible to SMX hypersensitivity reactions.PT: J; CR: CHAO ES, 1988, CELL BIOL TOXICOL, V4, P1 CRIBB AE, 1991, DRUG METAB DISPOS, V19, P900 CRIBB AE, 1991, J PHARMACOL EXP THER, V251, P1241 CRIBB AE, 1993, BIOCHEM PHARMACOL, V45, P1277 CRIBB AE, 1996, ADVERSE DRUG REACT T, V15, P9 CRIBB AE, 1996, CHEM RES TOXICOL, V9, P500 DUPRET JM, 1992, J BIOL CHEM, V267, P7381 KEARNS GL, 1994, J PEDIATR, V125, P805 LEE BL, 1994, CLIN PHARMACOL THER, V56, P184 NAKAMURA H, 1995, J PHARMACOL EXP THER, V274, P1099 PONSODA X, 1991, J TISSUE CULTURE MET, V13, P21 RIEDER MJ, 1989, ANN INTERN MED, V110, P286 RIEDER MJ, 1991, CLIN PHARMACOL THER, V49, P13 RILEY RJ, 1991, BIOCHEM PHARMACOL, V42, P696 SHEAR NH, 1986, ANN INTERN MED, V105, P179 SHEAR NH, 1988, J CLIN INVEST, V82, P1826 VANDERVEN AJA, 1995, BRIT J CLIN PHARMACO, V38, P147 WOLKENSTEIN P, 1995, PHARMACOGENETICS, V5, P255; NR: 18; TC: 5; J9: BIOMARKERS; PG: 6; GA: VV689Source type: Electronic(1
In-vitro formation, disposition and toxicity of n-acetoxy-sulffamethoxazole, a potential mediator of sulfamethoxazole toxicity
No full textVariation in the formation and disposition of the hydroxylamine of (SMX-HA) is thought to play an important role in the pathogenesis of sulfamethoxazole(SMX)-induced idiosyncratic adverse drug reactions. We hypothesized that, in analogy to carcinogenic arylamines, SMX-HA might be further converted to an electrophilic N-acetoxy metabolite which could play a role in mediating SMX toxicity. Accordingly, we chemically synthesized N-acetoxy-SMX, and examined the characteristics of its formation, metabolism, cytotoxicity and mutagenicity in human and bacterial test systems. The human arylamine N-acetyltransferases, (NAT)1 and NAT2, were capable of converting SMX-HA to N-acetoxy-SMX. NAT1 and NAT2 possessed similar affinities for SMX-HA (apparent K-m values of 650 and 520 mu M, respectively), but the apparent maximal velocity of the NAT1-mediated acetylation was higher than that of NAT2. (1332 vs. 37 nmol/min/U of immunoreactive NAT protein). Human peripheral blood mononuclear cells 12,000 x g supernatant fractions converted N-acetoxy-SMX mainly back to SMX-HA, and also to a lesser extent to SMX, at clinically relevant concentrations. Similar pathways were observed in human hepatic cytosolic fractions. In a cytotoxicity assay, N-acetoxy-SMX was significantly more toxic to human peripheral blood mononuclear cells than SMX-HA (16.6 vs. 11.5% dead cells at a concentration of 300 mu M). N-acetoxy-SMX was weakly mutagenic to the Salmonella typhimurium TA100 strain in the Ames test. These data suggest that the N-acetoxy metabolites of sulfonamides could potentially play a role in mediating sulfonamide idiosyncratic adverse drug reactions.PT: J; CR: BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248 CRIBB AE, 1990, DRUG METAB DISPOS, V18, P784 CRIBB AE, 1990, VET RES COMMUN, V14, P241 CRIBB AE, 1991, DRUG METAB DISPOS, V19, P900 CRIBB AE, 1991, J PHARMACOL EXP THER, V259, P1241 CRIBB AE, 1991, MOL PHARMACOL, V38, P744 CRIBB AE, 1992, CLIN PHARMACOL THER, V51, P522 CRIBB AE, 1993, BIOCHEM PHARMACOL, V45, P1277 DUPRET JM, 1992, J BIOL CHEM, V267, P7381 FAMULOK M, 1989, ANGEW CHEM INT EDIT, V28, P337 GRANT DM, 1990, J CLIN INVEST, V85, P968 GRANT DM, 1991, MOL PHARMACOL, V39, P184 GRANT DM, 1992, CANCER RES, V52, P1 HANNA PE, 1985, BIOACTIVATION FOREIG, P375 HEIN DW, 1987, CARCINOGENESIS, V8, P1767 HEIN DW, 1993, CARCINOGENESIS, V14, P1633 MCMANUS ME, 1989, CLIN EXP PHARMACOL P, V16, P491 RIEDER MJ, 1987, J PHARMACOL EXP THER, V244, P724 RIEDER MJ, 1989, ANN INTERN MED, V110, P286 RIEDER MJ, 1991, CLIN PHARMACOL THER, V49, P13 RILEY RJ, 1991, BIOCHEM PHARMACOL, V42, P696 SHEAR NH, 1985, CAN J PHYSIOL PHARM, V63, P1370 SHEAR NH, 1986, ANN INTERN MED, V105, P179 SPIELBERG SP, 1980, J PHARMACOL EXP THER, V213, P395 THOMPSON DC, 1992, MUTAT RES, V279, P83; NR: 25; TC: 21; J9: J PHARMACOL EXP THER; PG: 6; GA: RV893Source type: Electronic(1
Macvicaria adomeae Aken'Ova & Cribb & Bray 2008, n. sp.
No full textMacvicaria adomeae n. sp. Type-host: Sillaginodes punctatus (Cuvier) (Sillaginidae). Type-locality: Off American River, South Australia 35°48’S, 137°46’E. Site: Gut. Material studied: 9 Off American River, South Australia, December 1995. Type-material: Holotype: QM G 230424, paratypes: QM G 230425 - 230427, BMNH 2008.7.5.44-45. urn:lsid:zoobank.org:act: EBF2012C-678A-4BEA-8C97-5DE132F6AB60 Description (Figs 33-36) Based on 8 unflattened, whole-mount specimens and 1 set of serial sagittal sections and measurements of 5 gravid unflattened whole-mount worms. Body elongate, spindle shaped, maximum width in region of ventral sucker, 1,140 -1,578 (1,315) × 302-363 (331); width to length ratio 1:3.4-4.3 (4.0). Oral sucker globular, opening ventrally subterminal, 88-104 (95) × 98-110 (113). Ventral sucker transversely oval, in anterior third of body, 158-179 (167) × 181-213 (101); sucker width ratio 1:1.8-1.9 (1.9). Forebody 358-456 (396) long, 27-35 (30)% of body-length. Prepharynx short, dorsal to oral sucker. Pharynx subglobular, 48-59 (55) × 60-70 (65); pharynx to oral sucker width ratio 1:1.5-1.6 (1.6). Oesophagus distinct, short. Intestinal bifurcation in forebody, 107-166 (134) anterior to ventral sucker. Caeca terminate blindly close to posterior extremity. Excretory pore ventrally subterminal. Testes 2, oval, entire, contiguous to slightly separated, tandem, in posterior half of body, anterior 115-161 (136) × 121-145 (131), posterior 147-193 (166) × 121-159 (143). Post-testicular area 213-387 (300) long, 19-27 (23)% of body-length. Cirrussac elongate, clavate, thick walled, extends from point just posterior to posterior margin of pharynx, overlaps ventral sucker dorsally to its aperture (n=2), sometimes to level of (n=2) or posterior to posterior margin of ventral sucker (n=2), 303-412 (371) × 61-92 (74). Internal seminal vesicle tubular, sinuous, broadest at posterior end, fills broad posterior portion of cirrus-sac, surrounded by gland cells anteriorly. Pars prostatica distinct, thick walled, surrounded by gland cells. Ejaculatory duct long, thick walled. Genital atrium small. Genital pore antero-sinistral to intestinal bifurcation, midway between lateral margin and oesophagus, usually with cirrus protruding, (n=4), 189-209 (199) from anterior end, 13-18 (15)% of body-length. Ovary entire, spherical, contiguously anterior to or antero-dextral to anterior testis, 73-117 (89) × 78-115 (95). Mehlis’ gland indistinct, usually anterior to ovary, occasionally sinistral (n=1) to ovary. Canalicular seminal receptacle saccular, usually dorsal (n=4), sometimes antero-dextral (n=1), or sinistral to ovary, overlapping left side of ovary and anterior portion of anterior testis (n=1). Laurer’s canal present, opens dorso-sinistrally to ovary. Uterus coils intercaecally between anterior testis and ventral sucker, sometimes overlaps caeca ventrally, and ovary and testis dorsally, then passes to genital pore without coiling. Metraterm distinct, thick walled, overlaps left caecum. Eggs few, large, operculate, oval, 61-78 (70) × 28-50 (37). Vitelline follicles extend from 182-202 (194) from anterior extremity, 19-27 (23)% of body-length, to 11-38 (26) from posterior extremity; lateral fields may be continuous (n=3) or interrupted in ventral sucker area (n=3), ventral fields separate in forebody, and posteriorly to posterior margin of posterior testis, confluent or almost in post-testicular area; dorsal field confluent in forebody and post-testicular area always with continuous medial and sometimes bilateral or unilateral interruption in ventral sucker, uterine and gonad areas; follicles lie lateral, ventral and dorsal to caeca; anterior limit sometimes level with posterior end of oesophagus (n=3) or more anteriorly to point roughly level with mid-way between anterior and posterior ends of oesophagus (n=3). Excretory vesicle I-shaped, with narrow posterior end surrounded by few gland cells, passes anteriorly to point dorsal to posterior third of ovary. Etymology: This species is named for the mother of the first author. Comments: Macvicaria adomeae n. sp. can be accommodated in Group D as outlined above and can be distinguished from other species as follows: M. antarctica has a smaller pharynx, a shorter forebody at 26% of the body-length, a smaller post-testicular area and distinctly smaller eggs 42-51 × 20-28. M. georgiana has vitelline fields reaching to the pharynx, a saccular internal seminal vesicle, a shorter forebody (according to the illustrations in Zdzitowiecki, 1997) and small knobs on the anopercular pole of the eggs. M. issaitschikowi has a shorter forebody at 27% of the body-length, a slightly shorter post-testicular area of 19% of the body-length, a smaller pharynx, a larger ventral sucker, with a sucker width ratio of 1:2.61 versus 1:1.8-1.9 (1.9), smaller eggs 57-63 × 38-40, and its caeca terminate at about the level of the posterior margin of the posterior testis (Yamaguti, 1938) whereas they terminate well beyond the posterior margin of the posterior testis in M. adomeae. M. muraenolepidis has a saccular internal seminal vesicle and smaller eggs (36-50 x 21-32) with small anopercular knobs. M. heronensis can be distinguished by its slightly longer forebody at 35% of the body-length, a shorter post-testicular area at 19% of the body-length, longer and narrower eggs at 68-84 × 29-32 (76 × 31), the posterior extent of the uterus, the gonads which are situated more posteriorly and a genital pore closer to the anterior end.Published as part of Aken'Ova, Thelma, Cribb, Thomas & Bray, Rodney, 2008, Eight new species of Macvicaria Gibson and Bray, 1982 (Digenea: Opecoelidae) from temperate marine fishes of Australia, pp. 23-58 in ZooKeys 1 on pages 48-50, DOI: 10.3897/zookeys.1.8, http://zenodo.org/record/57639
Endoplasmic reticulum stress proteins in chemically mediated cytotoxicity
No full textEndoplasmic reticulum (ER) stress proteins appear to play a role in chemically induced idiosyncratic and direct hepatocellular cytotoxicity. Circulating antibodies directed against ER stress proteins can be found in patients suffering from idiosyncratic adverse drug reactions (ADR) to halothane and sulfamethoxazole. What if any pathological role these proteins or antibodies against them play in these reactions is not clear. In contrast to the potential deleterious involvement of ER stress proteins in idiosyncratic adverse drug reactions, there is substantial evidence that the expression of these ER stress proteins can confer protection against direct toxicity in a number of cell lines. In spite of the central role of hepatocytes in drug metabolism resulting in high exposures to reactive intermediates (RI), no data exists on the protective role of ER stress proteins in hepatocytes.Antibodies to ER stress proteins as well as organ toxicity are reported in immune-mediated ADR to sulfonamides and in the Long Evans Cinnamon (LEC) rat strain. It is not what, if any, role these circulating antibodies play in the accompanying toxicities. To investigate this, the onset of histological and biochemical evidence of liver damage in the LEC rat was compared temporally with the onset of circulating antibodies to ER proteins. In this study, toxicity was found to occur in the absence of these antibodies.This work expands existing knowledge of the protective effects of ER stress proteins. The expression level of ER stress proteins was pharmacologically increased in the porcine kidney cell line LLC-PK1, the human hepatocyte cell line HepG2 and the rat hepatocyte cell line H4IIE. In contrast to the broad protection ER stress proteins confer to the kidney cell line LLC-PK1, it was demonstrated for the first time that ER stress provides only limited protection to human and rat hepatocytes. This limited hepatocellular protection was further explored by examining the effect of ER stress protein induction on calcium disturbances evoked by model toxins. The toxins differed in their effect on cytosolic calcium and pre-ER stress prevented the rise in cytosolic calcium. Finally, the protective effects of one specific ER stress protein, protein disulfide isomerase (PDI), was considered by developing kidney and hepatocyte cell lines that over-express the protein. In both transient and stable overexpressing cell lines, there was a production of the transfected mRNA, but there was no detectable increase in the expression of the PDI protein, therefore no conclusions could be drawn regarding the ability of this ER stress protein to confer cytoprotection against RI.Source: Dissertation Abstracts International, Volume: 64-07, Section: B, page: 3204.Adviser: Alastair Cribb
Calpain-induced endoplasmic reticulum stress and cell death following cytotoxic damage to renal cells
No full textCalpains and endoplasmic reticulum (ER) stress have both been implicated in renal cell death following exposure to reactive chemical toxicants (RCTs). Therefore, we explored the link between ER stress, calpain, and cell death in renal cell injury due to model RCTs (iodoacetamide, menadione, tert-butyl hydroperoxide) and ER stress inducers (tunicamycin [TUN], thapsigargin [THAPS]). The calpain inhibitor, PD150606, significantly reduced the RCT and TUN-induced cell death in the renal cell line LLC-PK1, but not death induced by THAPS. ER stress was confirmed by the significant induction of GRP78 following exposure to RCTs and ER stress inducers. While GRP94 induction was observed following RCTs and TUN, it was not statistically significant because of variability. THAPS at 5 microM significantly induced GRP94, while 20 mmicroM caused a calpain-dependent cleavage of GRP94. Caspase-12 and m-calpain were variably induced and/or cleaved following exposure to all toxicants, supporting activation of these signaling pathways. Inhibition of calpain blocked the induction of GRP78 following exposure to RCTs suggesting that calpain was contributing to the observed ER stress following RCTs. In contrast, calpain inhibition did not block ER stress protein induction following exposure to nontoxic concentrations of TUN or THAPS, indicating that calpain inhibition did not block the ER stress protein induction pathways directly. These studies demonstrate a previously unappreciated link between calpain activation and ER stress-associated cell death in renal cells. While further studies are required to clarify the molecular events involved, these results confirm that calpain activation and the ER are important related players in chemically induced renal cell damage.PUBM: Print-Electronic; DEP: 20060818; JID: 9805461; 2006/08/18 [aheadofprint]; ppublishSource type: Electronic(1
Novel non-labile covalent binding of sulfamethoxazole reactive metabolites to cultured human lymphoid cells
No full textSulfamethoxazole (SMX) causes rare hypersensitivity syndrome reactions characterized by fever and multi-organ toxicity. Covalent binding of SMX reactive metabolites to cellular proteins has been demonstrated but the link between cytotoxicity and targets of covalent binding has not been explored. We therefore investigated the relationship between covalent binding of the reactive SMX-hydroxylamine (SMX-HA) metabolite, and its cytotoxicity to a hystiocytic lymphoma (U937) cell line. Incubation of U937 cells with 0-1 mM SMX-HA for 3 h resulted in dose-dependent cytotoxicity, as assessed by tetrazolium dye conversion at 24 h. SMX-HA caused dose-dependent covalent binding to cellular proteins as assessed by immunoblotting with SMX antisera at 3 and 24 h. Covalent binding was predominantly to proteins of approximately 45, 59 and 75 kDa, but other targets were also observed. The relative extent of binding to proteins was significantly different from the relative cytotoxicity at 24 h. Further, cells surviving at 24 h also had extensive covalent binding. Covalent binding was observed under reducing (beta-mercaptoethanol) and non-reducing conditions to plasma membrane and microsomal but not cytosolic proteins. This non-labile covalent binding has not been previously reported. These observations suggest that extensive covalent binding does not necessarily lead to cell death, allowing the accumulation of potentially immunogenic drug-protein conjugates. These observations in whole cells may be relevant to the immunopathogenesis of SMX hypersensitivity syndrome reactions.LR: 20061115; PUBM: Print; JID: 0227276; 0 (Anti-Infective Agents); 0 (Antibodies); 0 (Tetrazolium Salts); 0 (Thiazoles); 114438-33-4 (sulfamethoxazole hydroxylamine); 298-93-1 (thiazolyl blue); 723-46-6 (Sulfamethoxazole); ppublishSource type: Electronic(1
The Long Evans Cinnamon (LEC) rat develops hepatocellular damage in the absence of antimicrosomal antibodies
No full textPT: JSource type: Electronic(1
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