In vitro Anti‐human Immunodeficiency Virus Type 1 Activity of Biliverdin, a Bile Pigment

Mori, Haruyo; Otake, Toru; Morimoto, Motoko; Ueba, Noboru; Kunita, Nobuharu; Nakagami, Tatsuyoshi; Yamasaki, Non; Taji, Shiro

doi:10.1111/j.1349-7006.1991.tb02698.x

Cited by 30 publications

(28 citation statements)

References 5 publications

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“…HO-1 catalyzes the initial and rate-limiting step in the oxidative degradation of heme into biliverdin, free iron, and carbon monoxide [58]. The products of heme catabolism, bilirubin, and biliverdin have been demonstrated to inhibit HIV and SIV infection in vitro, presumably by inhibiting the protease activity and preventing viral entry [64,65]. Although the exact mechanism is not known, the induction of HO-1, by virtue of its anti-inflammatory and antiapoptotic properties, together with the production of biliverdin and bilirubin, could function as a potent inhibitor of HIV-1 replication.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction

Devadas

Hewlett

Dhawan

2010

Journal of Leukocyte Biology

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LPS is an important component of the Gram-negative bacteria cell wall. It activates monocytes and induces multiple host immune and inflammatory responses. Interestingly, in spite of inducing host-inflammatory responses, LPS also protects monocyte-derived macrophages from infection by HIV-1. In this report, we have shown that LPS treatment of human monocyte-derived macrophages markedly suppressed HIV-1 replication, even on addition to infected cells 24 h after infection. Inhibition of HIV-1 replication was associated with PKC-dependent induction of HO-1, a cytoprotective enzyme known to catabolize heme. Pretreatment with the PKC inhibitor Go 6976 not only substantially inhibited LPS-mediated induction of HO-1 but also attenuated LPS-induced suppression of HIV replication. Significant reduction of HIV replication by inhibitors of JNK, NF-kappaB, and PI3K was independent of a LPS-mediated anti-HIV effect. Specificity of HO-1 was confirmed by substantial reversal of LPS-induced viral replication by pretreatment of cells with SnPP IX, an inhibitor of HO-1 enzyme activity. These results demonstrate a previously undefined function of HO-1 as a host defense mechanism in LPS-mediated inhibition of HIV-1 replication.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction

Devadas

Hewlett

Dhawan

2010

Journal of Leukocyte Biology

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“…In our discussion, "bridging propionates" refers to propionate side chains at positions C 8 and C 12 , effectively bridging the central methene bridge. The verdins substituted at C 10 (13)(14)(15)(16) showed no change in the visible spectrum, which is not surprising because they are not reducible at C 10 . Unfortunately, none of these compounds are particularly effective inhibitors of BVR-A or BVR-B (which might have been a starting point for anti-hyperbilirubinaemia therapy).…”

Section: Substrate Specificity Of Biliverdin Reductases 19012mentioning

confidence: 94%

“…The Ah receptor is known to be involved in immunosuppression, and, during pregnancy, there is an increased susceptibility to certain types of infection (12)(13)(14). Both biliverdin-IX␣ and bilirubin-IX␣ have been implicated as modulators of the immune system (15,16). Intriguingly, the recent suggestion that indoleamine dioxygenase (EC 1.13.11.42) may be involved in fetal suppression of the maternal immune response (17) could also support Ah receptor involvement as tryptophan metabolites are also known to bind to and activate this transcription factor (18).…”

mentioning

confidence: 91%

Studies on the Specificity of the Tetrapyrrole Substrate for Human Biliverdin-IXα Reductase and Biliverdin-IXβ Reductase

Cunningham

Dunne

Sabido

et al. 2000

Journal of Biological Chemistry

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A comparison of the initial rate kinetics for human biliverdin-IX␣ reductase and biliverdin-IX␤ reductase with a series of synthetic biliverdins with propionate side chains "moving" from a bridging position across the central methene bridge (␣ isomers) to a "␥-configuration" reveals characteristic behavior that allows us to propose distinct models for the two active sites. For human biliverdin-IX␣ reductase, as previously discussed for the rat and ox enzymes, it appears that at least one "bridging propionate" is necessary for optimal binding and catalytic activity, whereas two are preferred. All other configurations studied were substrates for human biliverdin-IX␣ reductase, albeit poor ones. In the case of mesobiliverdin-XIII␣, extending the propionate side chains to hexanoate resulted in a significant loss of activity, whereas the butyrate derivative retained high activity. For human biliverdin-IX␣ reductase, we suggest that a pair of positively charged side chains play a key role in optimally binding the IX␣ isomers. In the case of human biliverdin-IX␤ reductase, the enzyme cannot tolerate even one propionate in the bridging position, suggesting that two negatively charged residues on the enzyme surface may preclude productive binding in this case. The flavin reductase activity of biliverdin-IX␤ reductase is potently inhibited by mesobiliverdin-XIII␣ and protohemin, which is consistent with the hypothesis that the tetrapyrrole and flavin substrate bind at a common site.

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“…Biliverdin is a biologically active compound that has been shown to inhibit viral replication in vitro (40). BVR is the enzyme responsible for the biotransformation of biliverdin to bilirubin and, along with heme oxygenase, is also found in a variety of tissues and organs.…”

Section: Discussionmentioning

confidence: 99%

Identification of Enzymes Responsible for the Metabolism of Heme in Human Platelets

Nowell¹,

Leakey²,

Warren³

et al. 1998

Journal of Biological Chemistry

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The major enzymes involved in the degradation of heme were identified in human platelets. It was determined that heme oxygenase activity levels in umbilical cord blood platelets were higher, whereas biliverdin reductase activity levels were comparable with that found in platelets from adults. In membranes prepared from adenosine diphosphate-activated platelets, UDP-glucuronic acid-dependent bilirubin conjugation was detected, whereas activity was negligible in unactivated platelets and undetected in serum and heat-inactivated platelets, and in platelets prepared from umbilical cord blood. Platelet fractions were analyzed by Western blot and shown to express heme oxygenase, biliverdin reductase, and UDP-glucuronosyltransferases, and there was concordance with known developmental profiles found in other tissues. Heme oxygenase expression was higher, whereas UGT expression was lower, in neonatal compared with adult platelets. These data suggest that platelets are involved in multiple steps of heme and bilirubin metabolism and that developmental regulation of these enzymes may be similar to that in other human tissues.

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In vitro Anti‐human Immunodeficiency Virus Type 1 Activity of Biliverdin, a Bile Pigment

Cited by 30 publications

References 5 publications

Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction

Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction

Studies on the Specificity of the Tetrapyrrole Substrate for Human Biliverdin-IXα Reductase and Biliverdin-IXβ Reductase

Identification of Enzymes Responsible for the Metabolism of Heme in Human Platelets

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