In vivo and in vitro effects of pentavalent antimony on mouse liver cytochrome P450s

Abstract

<jats:p> Pentavalent antimonial (Sb<jats:sup>5+</jats:sup>) drugs such as meglumine antimoniate (MA) are the mainstay treatment of leishmaniases in developing countries. The effects of these compounds on drug-metabolizing enzymes have not been characterized and their potential pharmacokinetic interactions with other drugs are therefore unknown. The present study investigated whether treatment with MA (300 mg Sb<jats:sup>5+</jats:sup>/kg body weight/day, subcutaneously) for 24 days affected the activities of cytochrome P450 (CYP)1A (ethoxyresorufin- O-deethylase), CYP2A5 (coumarin 7-hydroxylase), CYP2E1 ( p-nitrophenol-hydroxylase), CYP2B9/10 (benzyloxy-resorufin- O-debenzylase), or CYP3A11 (erythromycin- N-demethylase) in the livers of Swiss Webster (SW) and DBA-2 male and female mice. The results showed that CYP2A5-, CYP2E1-, and CYP3A11-catalyzed reactions were unaffected by MA treatment. A decrease in CYP2B9/10 activity was noted in DBA-2 females (but not males) and was not observed in SW males or females. However, repeated MA administration reduced mouse liver CYP1A activity. CYP1A2 messenger RNA (mRNA) levels were not affected by MA and in vitro exposure of mouse liver microsomes to Sb<jats:sup>3+</jats:sup> and Sb<jats:sup>5+</jats:sup> did not reduce CYP1A activity. These findings suggested that in vivo treatment with Sb<jats:sup>5+</jats:sup> drugs depressed CYP1A activity, without downregulating CYP1A2 mRNA expression. Since in vitro treatment of liver microsomes failed to inhibit CYP1A activity, this effect may require intact cells. </jats:p>

Biotransformation and tissue distribution of protopine and allocryptopine and effects of Plume Poppy Total Alkaloid on liver drug-metabolizing enzymes

“…The present study was designed to clarify the effect of Plume Poppy Total Alkaloid on ERND, ADM and NQO1 activity in female and male rats. ERND and AND were used as an indicator of CYP3A and CYPs catalytic activity, respectively 27 , 28 . Our group has demonstrated that NQO1 may be involved in isoquinoline alkaloid sanguinarine metabolism and decrease the toxicity of sanguinarine to cells 29 .…”

Study the Teratogenic Effect of Antimony on The Histological Changes of the Liver in the Adult Rabbit (Oryctolagus cuniculus)

“…Such scientific research is indispensable and pivotal for comprehending the environmental impact of antimony, as well as its effects on living organisms, akin to the scrutiny undertaken for other contaminants like pesticides [37,38]. The majority of histological investigations concerning the impact of antimony have predominantly centered on murine models, specifically rats [39] and mice [40]. However, a notable void exists in our understanding of the histological ramifications of this heavy metal on rabbits, where the effect known is for testes [41].…”

Leishmaniasis in humans: drug or vaccine therapy?

“…Although MA compounds are being used in different forms of leishmaniasis, several reports indicate that resistance to the MA drug has increased. 28 Earlier studies have shown that antimonials probably act with inhibiting glycolysis and fatty acid oxidation. 29 The conversion of Sb 5+ to Sb 3+ can produce strong toxicity to kill the parasite, but resistance to antimonials has also been described with impaired reduction of Sb 5+ to Sb 3+ .…”