Cytochrome P450-dependent arachidonic acid metabolism in human kidney

Cytochrome P450-dependent arachidonic acid metabolism in human kidney cortex from several postmortem subjects has been characterized. Using HPLC and GC/MS, four cytochrome P450-arachidonic acid metabolites were tentatively but not unequivocally identified as epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHT) and 19- and 20-hydroxyeicosatetraenoic acids, suggesting the involvement of two major cytochrome P450 enzymes, epoxygenase and omega/omega-1 hydroxylases. This pattern of metabolism was similar to that found in rabbit and rat kidneys. The formation of these metabolites was dependent on the presence of NADPH and inhibited by IgG of NADPH-cytochrome P450 (c) reductase. Immunologic studies of renal cytochrome P450 epoxygenase demonstrated that antibodies prepared against human-purified hepatic cytochrome P450 epoxygenase recognized renal enzyme protein and inhibited the enzyme activity by 92%. In contrast, control immunoglobulin did not inhibit renal cytochrome P450 epoxygenase. Antibody inhibition of renal cytochrome P450 epoxygenase demonstrated a degree of conservation of both enzyme proteins between liver and kidney. Antibodies against lauric acid omega/omega-1 hydroxylases (P450 omega) inhibited the formation of omega/omega-1 hydroxylase products, 19- and 20-HETEs. Identical qualitative patterns of arachidonic acid metabolites were observed in all cortical microsomes studied. Interindividual variations were observed in the cytochrome P450-dependent arachidonic acid metabolism, and the activities ranged from 0.031 to 5.027 nmol arachidonic acid converted/mg protein/30 min. which is about a 150-fold difference. However, when the specific activities for total cytochrome P450-dependent arachidonic acid metabolism were calculated, two separate groups could be distinguished, high and low metabolizers of arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absence of tobramycin pharmacokinetic and creatinine clearance variation during the menstrual cycle: implied absence of variation in glomerular filtration rate

During the menstrual cycle, a 20% increase in creatinine clearance (CL(CR] has previously been reported between the menstrual (phase 1) and late luteal (phase 4) phases. Tobramycin pharmacokinetics and CL(CR) were studied in eight healthy women with documented, regular, ovulatory menses. During the first and fourth phases of the menstrual cycle (as determined by urinary luteinizing hormone peak and basal body temperature shift), subjects received tobramycin by intravenous bolus. Tobramycin half-life, total body clearance, and volume of distribution were not significantly different between the two study phases. No significant change in total urinary creatinine excretion or CL(CR) was seen between phases. Total 24 hour urinary recovery of tobramycin was 98-99.7%. We conclude that no significant changes in renal function, as evaluated by tobramycin pharmacokinetics and CL(CR), occur between these hormonally different phases of the menstrual cycle, and that urinary recovery of a single dose of tobramycin is nearly complete within 24 hours in premenopausal women with normal renal function.     

Reflex sympathetic dystrophy and causalgia.

Converging lines of research suggest that RSD is a form of reflex neurogenic inflammation. Early the sympathetic nervous system appears to have an initiating and sustaining role. In later states of the illness, structural changes at the DH level seem to correlate with centralization of the process. Neuropeptides and EAAs released from thin or unmyelinated nociceptive afferents may produce both the inflammation and the suspected central sensitization of DH neurons seen in later stages of the disease. Effective treatment will follow a clearer understanding of the physiology of each stage of the disease.     

Acute Cellular Rejection Predominated by Monocytes Is a Severe Form of Rejection in Human Renal Recipients With or Without Campath-1H (Alemtuzumab) Induction Therapy

Campath-1H has been used successfully for induction and has resulted in a low rate of acute cellular rejection (ACR) in renal transplantation in combination with various postoperative immunosuppression regimens. This study was undertaken to investigate the extent of monocyte involvement in ACR, with or without Campath-1H induction. We found that monocytes represented the majority of inflammatory cells in grades Ib or higher ACR, but not with Ia type of ACR, regardless of the status of Campath-1H induction. Cases of ACR, following Campath-1H induction, appear to demonstrate a 'pure form' of monocytic ACR, whereas monocytes were mixed with many other types of inflammatory cells in the cases of ACR in the absence of Campath-1H induction. In addition with Campath-1H induction, the cases of monocyte-predominant ACR were found to uniformly exhibit a good response to corticosteroid treatment. We conclude that monocyte-predominate ACR may represent a severe form of rejection, with or without Campath-1H treatment.     

Effects on Fertility of Rabbits After Active Immunization With Rat Testicular Cytochrome ct

ABSTRACT: A Male rabbit was immunized with rat testicular cytochrome (Cyt) c_t and mated with normal, unimmunized females. The matings resulted in abnormal pregnancies: no offspring or stillborn or undersized liveborn offspring weighing 25–30 gm each. Another unusual observation was that fur-pulling behavior, normally exhibited by pregnant female rabbits at the end of the gestational period, was absent in all of these pregnancies. Therefore, immunization of a normal rabbit with testicular cyt c_t appeared to interfere with physiological and behavioral aspects of pregnancy in normal female rabbits. The immunological basis of these findings remains to be determined.     

Canine reaginic antibody. Characterization of the spontaneous anti-ragweed and induced anti-dinitrophenyl reaginic antibodies of the atopic dog

Anti-2,4-dinitrophenyl reaginic antibody has been induced in the atopic dog and compared with anti-ragweed reaginic antibody of spontaneous canine atopic hypersensitivity. Immunization of an atopic dog with ragweed hypersensitivity with dinitrophenylated ragweed pollen produced a high and sustained level of canine reaginic anti-DNP antibody. The induced and spontaneous forms of canine reaginic antibodies were shown to be identical in heat lability, sulfhydryl sensitivity, molecular size, charge, in their ability to remain fixed at passively-sensitized dermal sites for a prolonged period, and in their capacity to sensitized homologous white blood cells from normal donors for an immunospecific release of histamine. The induced anti-DNP and spontaneous anti-ragweed reaginic antibodies were physically separated and immunochemically differentiated from six other classes of canine immunoglobulins: γ2a, γ2b, γ2c, γ1, γA and γM, and shown to be members of a distinct class of canine immunoglobulins analogous to human γE (IgE).A high incidence of spontaneous atopic hypersensitivity has been observed in the progeny of the atopic dog.