Glutathione, protein sulfhydryls and cysteine proteases in gastric mucosal injury and protection.

Glutathione is one of the endogenous protective chemicals, like prostaglandins, in the gastric mucosa. Depletion of these agents aggravate the chemical- or stress-induced gastric erosions and ulcers. However, gastroprotection can be achieved even in the presence of low mucosal concentration of glutathione and prostaglandins, indicating the presence of other protective chemicals (e.g. polyamines, growth factors, neurotransmitters, steroids) in the stomach. Protein sulfhydryls were also implicated in the mechanism of action of gastroprotective drugs. We recently tested the hypothesis that cysteine proteases might be a target of gastroprotective and antiulcer agents, and decided to look for the presence of proteases and protease inhibitors (PI) in the gastric mucosa and juice. Protease activity and PI were measured with general substrates hemoglobin, azocasein and albumin at optimal pH (2.0, 5.6, 7.4) of aspartic, cysteine and serine proteases. Homogenates of glandular stomach mucosa and gastric juice from fasted rats were incubated in the presence or absence of specific inhibitors and gastroprotective SH alkylators such as NEM or iodoacetate. PI was measured after acid and heat inactivation of endogenous proteinases and addition of pepsin, cysteine proteinase papain, or trypsin. Our results indicate that of the proteases found in the stomach 98% was pepsin at pH 2.0, and up to 56% or 24% was SH-sensitive at pH 5.6 or 7.4, respectively. Intragastric administration of SH alkylators such as NEM or iodoacetate exerted a dose- and time-dependent gastroprotection against chemically induced acute erosions and ulcers. Thus, in addition to glutathione, proteinases and their specific endogenous inhibitors may also be involved in gastric mucosal injury and protection.