Biochemical effects of miconazole on fungi. II. Inhibition of ergosterol biosynthesis in Candida albicans.

The effects of the antifungal agent miconazole nitrate on the ergosterol biosynthesis in Candida albicans were investigated after in vitro contact with the drug for 1, 4, 16 and 24 h. A time- and dose-(2.10^?10–10^?4 M) dependent inhibition of [¹⁴C]acetate incorporation into ergosterol was observed. Fifty percent inhibition of the acetate incorporation into ergosterol was found after 1 h incubation in the presence of 10^?9 M miconazole. Simultaneously 24-methylenedihydrolanosterol, lanosterol, obtusifoliol, 4,14-dimethylzymosterol and 14-methylfecosterol accumulated.The accumulation of 14 α-methyl sterols suggests that this antifungal agent is a potent inhibitor of one of the metabolic steps involved in the demethylation at C-14. The absence of 24-methyl sterols and of sterols with a C-22 [23] double bond in miconazole treated C. albicans indicates that miconazole also inteferes with the reduction of the 24(28)-double bond and with the introduction of the 22(23)-double bond.Miconazole also intervenes to a small extent in triglyceride synthesis. However, in all circumstances studied, ergosterol biosynthesis was affected at lower doses than those interfering with the acetate incorporation into triglycerides. 16 and 24 h of incubation in the presence of miconazole (≥ 10^?6 M) also resulted in an increased fatty acid synthesis.It is suggested that the miconazole-induced inhibition of the C-14 demethylation may be at the origin of the previously observed permeability changes in miconazole treated C. albicans.     

Evidence for the involvement of a rapidly turning over protease in the degradation of cytochrome oxidase in Neurospora crassa

The reaction of L-aromatic aminoacid decarboxylase (EC 4.1.1.28) with α-methyl-L-DOPA or 5-hydroxy-L-tryptophan leads to the formation of dihydroxyphenylacetone or, respectively, 5-hydroxyindolacetaldeyde. These are produced in amounts far exceeding, on molar basis, that of the coenzyme, pyridoxal-5′-phosphate. The reaction cannot therefore be simply a decarboxylation-dependent transamination, using the coenzyme as an amino group acceptor. Evidence is presented which rules out the possibility that this phenomenon is due to an oxidative deamination.     

Risks and costs to human health of sulfide-ore mining near the Boundary Waters Canoe Area Wilderness

Abstract

Sulfide-ore copper nickel (SOCN) mining is being considered in water-rich Minnesota. Given pollution resulting from SOCN mining elsewhere, careful scrutiny is necessary examining the risks associated. Health considerations of mining within the Rainy River Watershed, the geographic region at the headwaters of the Boundary Waters Canoe Area Wilderness (BWCAW), Ontario’s Quetico Park (Quetico), and Voyageurs National Park (VNP) are examined. This discussion considers toxins released from SOCN mining, examines data regarding degradation of water quality and deleterious environmental impact from SOCN mining elsewhere, considers the most vulnerable populations, and recognizes the broader effects to public health as well as benefits of existing wilderness. Recent federal decisions to reinstate mineral leases and abort the environmental assessment process have placed this unique and irreplaceable region of our country at substantial risk. The overall health and wellness of this region will very likely be negatively affected by SOCN mining, and economic costs will predictably outweigh benefits. In addition, negative impacts on water, fish and wild rice will likely degrade nutritional and tribal resources resulting in violation of usufructuary rights of tribal communities.     

A First Exploration of Health Impact Assessment of Chemical Exposure: Assigning Weights to Subclinical Effects Based on Animal Studies

Health impact assessments (HIA) have become an important tool for applying evidence-based policy. Recently, the concept of HIA has been introduced in the field of chemical substances. Two main issues are encountered, i.e., the focus of risk assessment is deriving safe levels and on first signs of adverse effects. These adverse effects, often at a subclinical level, fall outside the scope of a HIA. However, the number of subjects with subclinical effects can be extensive, thus relevant to consider in HIA and subsequent risk management policies and socioeconomic analyses (e.g., under REACH). The approach to include subclinical effects in a HIA relies on the dose–response relationship for toxicological endpoints, which are indicative for subclinical and clinical effects. Assessment of (sub)clinical effect sizes requires expertise from toxicologists, pathologists, and risk assessors. The clinical effect is appraised by a disability weight in the disability adjusted life year (DALY) concept. Subsequently, a derivative thereof, the severity weight, is assigned to parameter value changes in the range of subclinical effect sizes to appraise subclinical effects. Ultimately, if the approach is repeated for many substances, severity weights may be assigned based on changes in endpoints alone, making it a valuable tool for health impact assessors of chemical substances.