Biology Reference
In-Depth Information
metabolism of endogenous compounds, such as steroid hormones. In the following
sections, the discussion and examples will serve to illustrate these various interactions.
Although the mechanisms of enzyme inhibition and induction are investigated by a
variety of biochemical and molecular biological techniques, it is important, for consider-
ation of the implications of these phenomena in human health risk assessment, to dem-
onstrate them in vivo. Some examples of methods and chemicals used for this purpose
are shown in Table 7.1 .
INDUCTION
Induction of Microsomal Enzyme Activity
The stimulatory effect of xenobiotics on liver microsomal enzymes was first reported
in the 1950s ( Brown et al., 1954; Conney et al., 1957; Miller et al., 1954; Remmer,
1958 ) and since then has been extensively investigated. Numerous early experiments
with laboratory rodents confirmed hepatic enzyme induction, although until recently
methods were not available for identification of individual isoforms and the inducer
was often classified as a phenobarbital-, a 3-methyl-cholanthrene-, or a mixed-type
inducer. Reviews in this area include those of Conney (1967) , Gelboin and Conney
(1968) , Sher (1971) , Gillette et al. (1972) , Nebert and Jensen (1979) , Okey et al. (1986) ,
Okey (1990) , Batt et al. (1992) , and Denison and Whitlock (1995) . Reviews with
emphasis on pesticides include those of Fouts (1963) , Conney et al. (1967) , Leibman
(1968) , Street et al. (1969) , DuBois (1969) , Hodgson (1974) , Hodgson and Kulkarni
(1974) , Hodgson et al. (1980) , Wilkinson and Denison (1982) , Khan (1984) , Kulkarni
and Hodgson (1984a,b) , Hodgson and Levi (1996) , and Hodgson and Meyer (1997,
2010) . It should be noted that induction is not restricted to xenobiotics, and enzymes
may also be induced by hormones and other normal body constituents ( Conney, 1967;
Conney et al., 1967, 1979; Kobliakov et al., 1991; Pantuck et al., 1979, 1984; Ronis
and Cunny, 1994; Schenkman et al., 1989 ) and by dietary constituents ( Anderson and
Kappas, 1991; Donaldson, 1994 ; Hodgson and Meyer, 2010; Wattenberg, 1971 ).
More recently, human hepatocytes have been used as a model system for investigat-
ing the induction of microsomal monooxygenases and other XMEs by pesticides (e.g.,
Das et al., 2006, 2008a,b ).
A large number of studies have provided evidence for induction of enzymes in
surrogate animals, or in humans who have been exposed occupationally or environ-
mentally to pesticides ( Table 7.2 ). For the most part these studies employed noninvasive
in vivo techniques such as examination of the half-life of aminopyrene or phenyl-
butazone or excretion of 6β-hydroxycortisol ( Guzelian et al., 1980; Kolmodin et al.,
1969; Kolmodin-Hedman, 1973; Kreiss et al., 1981; Poland et al., 1970 ). More recently,
in vitro techniques have been used following in vivo exposure, techniques that yield
information on such aspects as isoform specificity and the mechanism of induction.
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