Mercury sulfides are much less nephrotoxic than mercury chloride and methylmercury in mice

Abstract

Mercury sulfides (α-HgS, β-HgS) are frequently included in traditional medicines. Mercury is known for nephrotoxicity, their safety is of concern. To address this question, mice were orally administrated with Zuotai (54% β-HgS, 30mg/kg), α-HgS (HgS, 30mg/kg), HgCl (33.6mg/kg), or MeHgCl (3.1mg/kg) for 7days, and nephrotoxicity was examined. Animal body weights were decreased by HgCl and to a lesser extent by MeHg, but unaltered after Zuotai and HgS. HgCl and MeHg produced renal tubular vacuolation, interstitial inflammation and cell degeneration with protein cysts in the tubular lumen, while these pathological lesions were mild in Zuotai and HgS-treated mice. Electron microscopy showed that HgCl and MeHg produced spotted swelling endothelium reticulum, while these lesions were mild or absent in Zuotai and HgS-treated mice. Renal Hg contents reached 250-300ng/mg kidney in HgCl and MeHg groups as compared to 2-3ng/mg in Zuotai and HgS groups. The expression of kidney injury biomarkers, kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (Ngal), were increased after HgCl and MeHg, but unaltered after Zuotai and HgS. The expression of renal influx transporters Oat3 and Oatp4c1 was decreased, while the expression of renal efflux transporter such as Mrp2, Mrp4, and Mate2 was increased following HgCl and MeHg. These gene expressions were unchanged after Zuotai and HgS. In summary, both α-HgS and β-HgS are less nephrotoxic than HgCl and MeHg, indicating that chemical forms of mercury are a major determinant of mercury disposition and toxicity.

Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan (Rannasangpei) differs from mercury chloride and methylmercury on hepatic cytochrome P450

“…Brie y, 70W at 1 to 5-fold clinical doses and Zuotai (30 mg/kg, po) for 7 days did not produce signi cant effects on the liver CYP450 gene and protein expressions; while HgCl 2 at equivalent Hg dose increased the expression of CYP1A, CYP2B, CYP2E1, and CYP7A at the transcription and/or protein levels, MeHg at 1/10 Hg dose produced similar effects, but to a lesser extent. These results further demonstrated that chemical forms of metals are a major determinant of their biological effects [24][25][26][27][29][30][31].…”

“…Mice were given oral administration for consecutive 7 days. The dose regimen selection was based on our prior publications [8,11,[24][25][26][27]. Livers were collected 24 h after the last dose and stored at -80°C prior to analysis.…”

“…Zuotai is included in 70W in a small amount [2][3][4]8]. The chemical speciation, spatial distribution of mercury from Zuotai are different from that of HgCl 2 [7,18], resulting in differential toxicity when compared to environmental mercury compounds (HgCl 2 and MeHg) in experimental animals and cultured human cells [24][25][26][27][29][30][31]. In patients taking Zuotai-containing Tibetan medicines, mercury toxicity to the liver and kidney was mild, tolerable and reversible [10,[21][22][23].…”

“…A recent human study revealed that Zuotai-containing Tibetan medicines are safe at clinical doses [19,21,22], including 70W [23]. Indeed, Zuotai differs from HgCl 2 and MeHg in producing hepatotoxicity [24], nephrotoxicity [25,26], and intestinal toxicity with gut microbiome disruptions [27]. Whether Zuotaicontaining 70W has any effect on CYP450 in comparison with mercury compounds is worth of investigation.…”

Peer Review #1 of "The Tibetan medicine Zuotai influences clock gene expression in the liver of mice (v0.1)"

“…Modern analytical methods show that Zuotai contains mainly β-HgS, and other trace elements (Li et al, 2015) . In experimental animals, Zuotai at 4.5fold of clinical dose (30 mg/kg) did not show overt toxicity towards the kidney and liver as compared to HgCl 2 (at equivalent Hg dose) or MeHg (at 1/10 Hg dose) (Lu et al, 2015). In a recent clinical trial, Zuotai-containing Danzuo did not show obvious adverse effects in patients under the clinical doses and duration of administration .…”