E-Letter responses to:

brevia: Eric Blackstone, Mike Morrison, and Mark B. Roth H2S Induces a Suspended Animation–Like State in Mice Science 2005; 308: 518 [Abstract] [Full text] [PDF]

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Published E-Letter responses:

Reflections on the purpose of oxygen consumption

James A Timmons   (3 June 2005)

Toxicant-induced regulated hypothermia

Christopher J. Gordon   (24 May 2005)

Hydrogen sulfide is also highly toxic

Heikki E Savolainen   (24 May 2005)

Reflections on the purpose of oxygen consumption 3 June 2005
James A Timmons Karolinska Institute Respond to this E-Letter: Re: Reflections on the purpose of oxygen consumption	I found the article by Blackstone and colleagues intriguing (1). It made me question how much of the oxygen consumed, by a mouse at "rest," is actually coupled to ATP regeneration and hence how relevant it might be to draw parallels to humans. Indeed, this question reflects the dilemma of how useful murine models of metabolism may be for the study of human metabolic disease if "regulation" can be so fundamentally geared toward differing metabolic objectives. A mouse typically has a body mass 1/3000th of a adult human. A mouse also has a heart rate that is 14 times greater and respiratory rate approximately 10 times faster than a human. While a human typically consumes ~3ml/min/kg Oxygen at rest (2), a mouse may consume anything from 30 to 50 ml/min/kg (partly reflecting that they are not truly at "rest") (3). Gordon has made the point that much of the oxygen consumed reflects the requirement for heat generation in small mammals. What might also be concluded is that by reducing oxygen consumption by ~90% [e.g., Fig A (1)], ATP requiring processes (e.g. ion homeostasis) are not dramatically compromised in the mouse but rather H2S is "selectively" influencing the component of mitochondrial oxygen consumption connected with mitochondrial uncoupling. Presumably as a degree of metabolic perturbation is "sensed" following H2S administration, the uncoupling process becomes inhibited, thus leading to relative preservation of ATP homeostasis. Given that the 90% reduction in oxygen consumption noted in the present study approximates the mouse to the human (on an O2 consumed per mass basis) and that mice rely on the same molecular substrates for ATP regeneration, it could be concluded that there may be little scope to compromise oxidative phosphorylation in a human in a manner directly analogous to this present study. References 1. E. Blackstone, M. Morrison, M. B. Roth, H2S induces a suspended animation-like state in mice, Science 308, 518 (2005). 2. J. Woo, T. Kwok, M. Kwan, The standard oxygen consumption value equivalent to one metabolic equivalent (3.5 ml/min/kg) is not appropriate for elderly people, Int. J. Food Sci. Nutr. 55 (no. 3), 179-82 (2004). 3. M. W. Merx, A. Godecke, U. Flogel, J. Schrader, Oxygen supply and nitric oxide scavenging by myoglobin contribute to exercise endurance and cardiac function, FASEB J., 7 April 2005.
Toxicant-induced regulated hypothermia 24 May 2005
Christopher J. Gordon, Research Physiologist U.S. Environmental Protection Agency Respond to this E-Letter: Re: Toxicant-induced regulated hypothermia	I found the paper describing suspended animation in the mouse induced by exposure to hydrogen sulfide to be interesting. However, I was surprised that the authors did not acknowledge the extensive data base on toxicant-induced hypothermia in rodents (1-4). The term “regulated hypothermia” was coined over 18 years ago to describe the nature of the thermoregulatory response of rodents exposed to a toxicant or drug that induces a regulated reduction in body temperature (1). During regulated hypothermia in rodents, there is a reduction in metabolic heat production, peripheral vasodilation, and/or behavioral selection of cooler ambient temperatures, all leading to a reduction in body temperature. It is well known that the toxicity of most chemicals is directly proportional to body temperature (1). Hence, it appears that rodents activate a regulated hypothermic response to improve their ability to recover from the toxic insults. Furthermore, drugs that can induce regulated hypothermia may be an ideal therapeutic method to treat victims of stroke and other ischemic diseases (6). To further support this point, a nontoxic chemical has already been shown to cause regulated hypothermia in rodents and appears to reduce brain damage when given after an hypoxic-ischemic event (7, 8). I agree with the authors that regulated induction of hypothermia could have medical benefits for a variety of conditions. However, researchers should be cautioned that, because of their relatively large surface area:mass ratio, rodents are capable of effecting a rapid reduction in core temperature when challenged with a toxic insult. This protective response is minimized in larger mammals (such as adult humans) with large thermal inertia and highly effective thermoeffectors that resist reductions in body temperature. References 1. Gordon, C.J., F.S. Mohler, W.P. Watkinson, A.H. Rezvani, Toxicolology 53, 161-178 (1988). 2. C. Watanabe, T. Suzzuki, Toxicol. Appl. Pharmacol. 86, 372- 379 (1986). 3. W. P. Watkinson, C. J. Gordon, Toxicology 81, 15-31 (1993). 4. C. J. Gordon, Temperature and Toxicology: An Integrative, Comparative, and Environmental Approach (CRC Press, Boca Raton, FL, 2005). 6. C. J. Gordon, Emerg. Med. J. 18, 81-89 (2001). 7. C. J. Gordon et al., Life Sci, 73, 2611-23 (2003). 8. L. M. Katz et al., Crit Care Med 32, 806-10 (2004).
Hydrogen sulfide is also highly toxic 24 May 2005
Heikki E Savolainen, physician Ministry of Social Affairs & Health, Tampere, Finland Respond to this E-Letter: Re: Hydrogen sulfide is also highly toxic	Having read the interesting article on the induction of an inactive state by hydrogen sulfide in mice, I would like to remind readers that the gas is also highly toxic because it is an inhibitor of the mitocondrial cytochrome oxidase, thereby causing histotoxic hypoxia resulting in death. Even nonlethal exposure is associated with marked mitochondrial effects in brain and in other highly oxygen-dependent organs (1). Fatal gassing incidents occur, e.g., in oil industry, pulp and paper plants, leather tanning, sewage work, and in conditions with anaerobic bacterial metabolism. 1. H. Savolainen, R. Tenhunen, E. Elovaara, A. Tossavainen, Cumulative biochemical effects of repeated subclinical hydrogen sulfide intoxication in mouse brain, Int. Arch. Occup. Environ. Health 46, 87-92 (1980).