Gender Differences in Microsomal Metabolic Activation of Hepatotoxic Clivorine in Rat

Lin, Ge; Cui, Yanyan; Liu, Xiaoquan

doi:10.1021/tx0340302

Cited by 47 publications

(45 citation statements)

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“…Moreover, an additional pathway was found in female rats to directly metabolize clivorine, which might be responsible for detoxification to produce non/less toxic metabolite(s). However, identity of such a pathway, the formed metabolite, and enzyme(s) involved were not investigated in our previous study (Lin et al, 2003). In the present report, the microsomal metabolic pathways of clivorine in female rats, the generated metabolites, and the enzymes mediating these pathways are described.…”

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confidence: 71%

“…Compared with male rats, significantly lower metabolic activation rate to form toxic pyrrolic ester was observed in the hepatic microsomal metabolism in female rats, although the overall metabolic rates of clivorine in both sexes of rats were the same (Lin et al, 2003). Moreover, an additional pathway was found in female rats to directly metabolize clivorine, which might be responsible for detoxification to produce non/less toxic metabolite(s).…”

Section: Introductionmentioning

confidence: 81%

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Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Lin

Tang²,

Liu³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Clivorine, a naturally occurring pyrrolizidine alkaloid, causes liver toxicity via its metabolic activation to generate toxic metabolite (pyrrolic ester). Female Sprague-Dawley (SD) rats are reported to be less susceptible to clivorine intoxication than male SD rats. However, the biochemical mechanism causing such gender difference is largely unknown. The present study investigated hepatic microsomal metabolism of clivorine in female rats to delineate the mechanism of the gender difference. Two pathways, which directly metabolize clivorine, were observed. First, the metabolic activation to produce the toxic pyrrolic ester followed by formations of bound pyrroles, dehydroretronecine, 7-glutathionyldehydroretronecine, and clivoric acid were found in female rats, and CYP3A1/2 isozymes were identified to catalyze the metabolic activation. Compared with male rats (ϳ21%), the metabolic activation in female rats was significantly lower (ϳ4%) possibly because of significantly lower CYP3A1/2 levels expressed in female rats. Second, a direct hydrolysis to generate the novel female rat-specific metabolite deacetylclivorine was shown as the predominant pathway (ϳ16% clivorine metabolism) in female rat liver microsomes and was determined to be mediated by microsomal hydrolase A. Furthermore, when the metabolic activation was completely inhibited by ketoconazole, the amount of deacetylclivorine formed in a 1-h incubation significantly increased from 19.44 ؎ 3.00 to 54.87 ؎ 9.30 nmol/mg protein, suggesting that the two pathways compete with each other. Therefore, the lower susceptibility of female SD rats to clivorine intoxication is suggested to be caused by the significantly higher extent of the direct hydrolysis and a lower degree of the metabolic activation.Pyrrolizidine alkaloid (PA) poisoning has drawn worldwide attention because of a wide distribution of PA-containing plants and their induced serious and diversified toxicities, especially hepatotoxicity and carcinogenicity (Mattocks, 1968;Mori et al., 1985;Huxtable, 1989;Buhler et al., 1990;Fu et al., 2002Fu et al., , 2004, as well as pneumotoxicity (Huxtable, 1990;Taylor et al., 1997), neurotoxicity (Roeder, 2000), and embryotoxicity (Tu et al., 1988). Two types of PA, namely, retronecine and otonecine, are mainly responsible for the PA-induced hepatotoxicity (Mori et al., 1985;Huxtable, 1989;Buhler et al., 1990;Fu et al., 2004). Clivorine, a representative toxic otonecine-type PA, is present in many Ligularia species and especially exists as a predominant PA in the traditional Chinese medicinal herb Ligularia hodgsonii Hook (Lin et al., 2000b;Xia et al., 2004). Clivorine has been reported to cause hepatotoxicity and carcinogenicity in rodents and a positive mutagenic response in the Ames test in the presence of rat liver homogenates, suggesting the importance of hepatic metabolic activation in its intoxication (Yamanaka et al., 1979;Kuhara et al., 1980;Xia et al., 2004). In our previous studies, hepatic microsomal metabolism of clivorine in male Sprague-Dawle...

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confidence: 71%

Section: Introductionmentioning

confidence: 81%

Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Lin

Tang²,

Liu³

et al. 2007

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

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“…So far, it has been reported that some of the alkaloids led to potential gender-dependent toxicities due to their gender-related pharmacokinetics (25)(26)(27)(28)(29). Male SD rats were shown to be more susceptible to clivorine (a pyrrolizidine alkaloid) intoxications than female rats due to the gender-associated metabolism (26)(27)(28). Therefore, the characterization of veratramine pharmacokinetic profiles of both gender, particularly in gender-related metabolism and elimination, is considered essential for the evaluation of its safety and potential interactions with other drugs or herbs.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

Lyu

Zhang

Zhou

et al. 2016

AAPS J

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ABSTRACT. Veratramine, a major alkaloid from Veratrum nigrum L., has distinct anti-tumor and antihypertension effects. Our previous study indicated that veratramine had severe toxicity toward male rats. In order to elucidate the underling mechanism, in vivo pharmacokinetic experiments and in vitro mechanistic studies have been conducted. Veratramine was administrated to male and female rats intravenously via the jugular vein at a dose of 50 μg/kg or orally via gavage at 20 mg/kg. As a result, significant pharmacokinetic differences were observed between male and female rats after oral administration with much lower concentrations of veratramine and 7-hydroxyl-veratramine and higher concentrations of veratramine-3-O-sulfate found in the plasma and urine of female rats. The absolute bioavailability of veratramine was 0.9% in female rats and 22.5% in male rats. Further experiments of veratramine on Caco-2 cell monolayer model and in vitro incubation with GI content or rat intestinal subcellular fractions demonstrated that its efficient passive diffusion mediated absorption with minimal intestinal metabolism, suggesting no gender-related difference during its absorption process. When veratramine was incubated with male or female rat liver microsomes/cytosols, significant malepredominant formation of 7-hydroxyl-veratramine and female-predominant formation of veratramine-3-O-sulfate were observed. In conclusion, the significant gender-dependent hepatic metabolism of veratramine could be the major contributor to its gender-dependent pharmacokinetics.

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“…The species-, strain-or gender-depending variations in enzymatic activities or expressions, resulting in different overall balances of the detoxification and activation pathways, can influence the higher susceptibility of certain animals (e.g. male rat > guinea pig) to PA toxicity (Huan et al, 1998a;Lin et al, 2002Lin et al, , 2003Chung and Buhler, 2004;Lin et al, 2007).…”

Section: Metabolismmentioning

confidence: 99%

Scientific Opinion on Pyrrolizidine alkaloids in food and feed

2011

EFS2

222

130

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The European Food Safety Authority (EFSA) was asked by the European Commission to deliver a scientific opinion on pyrrolizidine alkaloids (PA) in food and feed. PAs are toxins exclusively biosynthesised by plants. To date, approximately 600 different PAs are known. Results for 13,280 bulk honey and 1324 retail honey samples were provided to EFSA by one Member State and 351 feed samples were provided by a second Member State. The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) performed estimates of both acute and chronic exposure to PAs through honey for three different age groups. Although there might be other sources of PA exposure, due to lack of data the CONTAM Panel was not able to quantify dietary exposure from food other than honey. A number of PAs were identified as being of particular importance for food and feed. Based on the present knowledge of metabolism, activation, DNA adduct-formation, genotoxicity and carcinogenicity, the CONTAM Panel concluded that 1,2-unsaturated PAs may act as genotoxic carcinogens in humans. Therefore, the CONTAM Panel decided to apply the Margin of Exposure (MOE) approach. A benchmark dose lower confidence limit for a 10 % excess cancer risk (BMDL 10 ) of 70 µg/kg b.w. per day for induction of liver haemangiosarcomas by lasiocarpine in male rats was calculated as the reference point for comparison with the estimated dietary exposure. The CONTAM Panel concluded that there is a possible health concern for those toddlers and children who are high consumers of honey. There is generally a low risk of PA poisoning in livestock and companion animals in the EU as most PA poisonings reported recently are due to accidental exposure. © European Pyrrolizidine alkaloids in food and feedEFSA Journal 2011;9(11):2406 2 SUMMARYFollowing a request from the European Commission, the Panel on Contaminants in the Food Chain (CONTAM Panel) was asked to deliver a scientific opinion on the risks to human and animal health related to the presence of pyrrolizidine alkaloids (PA) in food and feed. PAs are toxins exclusively biosynthesised by plants. They are typical plant secondary metabolites against herbivores. It has been estimated that approximately 6000 plant species world wide, representing 3 % of all flowering plants, may contain pyrrolizidine alkaloids. PAs are mainly found in the distantly related angiosperm families of the Boraginaceae (all genera), Asteraceae (tribes Senecioneae and Eupatorieae) and Fabaceae (genus Crotalaria). The PA-content of plant material depends on a large number of factors (species, plant organ, harvest, storage, extraction procedures). Reported contents vary from trace amounts up to 19 % based on dry weight. The name pyrrolizidine is the chemical description of two-fused 5-membered rings with a nitrogen atom at the bridgehead. This motif is the central structure of a variety of PAs. PAs generally consist of an amino alcohol which is referred to as necine or necine base and an acid part which is called a necic acid. Most of the known PAs are este...

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Gender Differences in Microsomal Metabolic Activation of Hepatotoxic Clivorine in Rat

Cited by 47 publications

References 31 publications

Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

Scientific Opinion on Pyrrolizidine alkaloids in food and feed

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