Page 666 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxic Gases and Vapors Chapter | 48 631

VetBooks.ir regarded as being analogous to a “gas scrubber” that pre- pulmonary macrophages (although there are important
examples of metabolic toxication by type II pneumocytes
vents or limits the exposure of the deeper respiratory tract
and/or alveolar macrophages). The immunohistochemical
tissues (i.e., a protective mechanism). As with any “gas
scrubber,” the capacity to remove a gas from the inhaled distribution and biochemical activity of biotransformation
air can be “overcome” if the scrubbing capacity becomes enzymes in the rat nasal cavity are shown in Table 48.1.
saturated due to high concentrations and/or long durations As can be seen from the table, biotransformation potential
of exposure. As a general rule, gases that are poorly water is predominantly located in the olfactory and respiratory
soluble and are not highly reactive are generally poorly epithelia of the nasal cavity. Whether or not metabolism
absorbed/scrubbed out in the upper respiratory tract. A in the olfactory or respiratory epithelium predominates
further general rule is that relatively little gas exchange depends on which enzymes are involved and the particu-
occurs in the conducting airways (anatomic dead space) lar substrate. Although it is notable that both phase I and
areas of the respiratory tract. However, adverse site-of- phase II biotransformation reactions occur in the nasal
contact effects can certainly still occur in these anatomic cavity, the biotransformation capacity of the nasal cavity
dead spaces of the respiratory system. is a prime source of local toxication of many inhaled (and
noninhaled) xenobiotics (Bogdanffy, 1997).
Metabolism Numerous studies have demonstrated that club cells
are a rich source of cytochrome P450-dependent mixed-
Metabolism of gases can occur locally in the respiratory
function oxidases and a prime site for P450-mediated
tract or at other distant sites (discussed elsewhere in this
phase I metabolism and toxication in the lung (Devereux,
book). As a generalization, biotransformation of gases
1984; Devereux et al., 1985; Baron and Voigt, 1990;
within the respiratory tract primarily occurs at two main
Hukkanen et al., 2002; Castell et al., 2005).
locations: within the epithelia of the nasal cavity and
within the club cells of the lung (Bogdanffy et al., 1986,
1987; Castranova et al., 1988; Baron and Voigt, 1990; Excretion via the Respiratory Tract
Bogdanffy, 1990; Keller et al., 1990; Hukkanen et al., Simple single-phase excretion (single compartment kinet-
2002; Castell et al., 2005). Phase I biotransformation also ics) of inhaled gases through the respiratory tract is in
occurs to a lesser degree in type II pneumocytes and in many ways dependent on the same factors as gas

TABLE 48.1 Distribution of Biotransformation Enzymes in the Rat Nasal Cavity

Tissue Type AldH CarbE FdH NBE P450 red P450 EH GSHt BαPOH
Squamous Low No data No data Low No data No data No data No data No data
epithelium
Respiratory High High Present Moderate Present Present Present Present Present
epithelium
Seromucous No No data No data Low Present Present Present Present Present
glands data
Olfactory Absent Present in Present Moderate Present Present Present Present Present
sustentacular olfactory
cells mucosa
Olfactory Absent Present Absent Absent Absent Absent Absent Absent
nerves
Bowman’s Low Present High Present Present Present Present Present
glands
AldH, acetaldehyde dehydrogenase; CarbE, carboxylesterase; FdH, formaldehyde dehydrogenase; NBE, alpha-naphthyl butyrate esterase; P450 red,
NADPH cytochrome P450 reductase; P450, cytochrome P450s; EH, epoxide hydrolase; GSHt, glutathione-S-transferases; BαPOH, benzo(a)pyrene
hydroxylase.
Source: Data from Bogdanffy, M.S., Randall, H.W., Morgan, K.T., 1986. Histochemical localization of aldehyde dehydrogenase in the respiratory tract of
the Fischer-344 rat. Toxicol. Appl. Pharmacol. 82:560 567; Bogdanffy, M.S., Kee, C.R., Hinchman, C.A., Trela, B.A., 1991. Metabolism of dibasic esters by
rat nasal mucosal carboxylesterase. Drug Metab. Dispos. 19:124 129; Bogdanffy, M.S., 1990. Biotransformation enzymes in the rodent nasal mucosa: the
value of a histochemical approach. Environ. Health Perspect. 85:177 186 (Bogdanffy et al., 1991); Keller, D.A., Heck, H.D., Randall, H.W., Morgan, K.T.,
1990. Histochemical localization of formaldehyde dehydrogenase in the rat. Toxicol. Appl. Pharmacol. 106:311 326; Trela, B.A., Bogdanffy, M.S., 1991a
Carboxylesterase-dependent cytotoxicity of dibasic esters (DBE) in rat nasal explants. Toxicol. Appl. Pharmacol. 107:285 301; Trela, B.A., Bogdanffy, M.S.,
1991b. Cytotoxicity of dibasic esters (DBE) metabolites in rat nasal explants. Toxicol. Appl. Pharmacol. 110:259 267 (Trela and Bogdanffy et al., 1991a,b);
and Bogdanffy, M.S., Taylor, M.L., 1993. Kinetics of nasal carboxylesterase-mediated metabolism of vinyl acetate. Drug Metab. Dispos. 21:1107 1111
(Bogdanffy and Taylor, 1993).