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that occurs in neonatal development. This imprinting is brought about by a surge
of testosterone that occurs in the male neonate and appears to imprint the devel-
oping hypothalamus, so that in later development growth hormone is secreted in a
gender-specific manner. This pattern of growth hormone production is pulsatile and
the higher level of circulating testosterone in the male maintains the expression of
male-specific CYP isoforms such as 2C11. On the other hand, a more continuous pat-
tern of growth hormone secretion and the lack of circulating testosterone appear to
be responsible for female-specific CYPs such as 2C12 (
Gonzalez, 1989; Hosteter et al.,
1987; Kobliakov et al., 1991; Schenkman et al., 1989
).
Gender-specific expression is also seen with the FMO enzymes. It has been known
for some time that hepatic FMO activity is higher in female mice than in males, and
that the lower levels in males result from testosterone repression (
Dannan et al., 1986;
Duffel et al., 1981; Falls et al., 1997; Lemoine et al., 1991; Wirth and Thorgeirsson,
1978
). In addition, hormonal changes during pregnancy have been reported to increase
FMO levels (
Williams et al., 1985
). With regard to pesticide oxidation, gender differ-
ences have also been observed, with higher activity in female mouse liver than in male
(
Kinsler et al., 1988
).
Recent studies have identified FMO isozymes involved in these gender differences
and some of the hormonal factors involved in regulation. In several strains of mouse
liver, FMO1 expression was found to be two to three times higher in female mice
compared to males, and FMO3, expressed in females at levels comparable to FMO1,
was not detectable in male liver (
Falls et al., 1995, 1997; Cherrington et al., 1998a
). In
rat liver, however, FMO1 is higher in the male, whereas FMO3 is gender-independent
in both rats and humans. FMO5 is gender-independent for the mouse, rat, and human
(
Cherrington et al., 1998a
).
Genetic Factors
The existence of discontinuous or biphasic variation is a strong indication of the pos-
sibility of genetic involvement. Some examples are given here in which such variation
in enzyme activity within populations has been proven to be genetic in origin.
The fungicide ziram caused hemolytic anemia with Heinz body formation in a man
later shown to be deficient in erythrocyte glucose-6-phosphate dehydrogenase. Ziram
also caused one of the typical in vitro reactions, formation of Heinz bodies, in the
blood of another person known to be deficient in this enzyme (
Pinkhas et al., 1963
).
Many of the phenotypic variations in drug responses observed in human popula-
tions have been shown to result from polymorphisms in the expression of the xenobi-
otic-metabolizing enzymes (for reviews see
Smith et al., 1994a,b; Kalow, 1991; Coutts
and Urichuk, 1999; and Wormhoudt et al., 1999
). Many human CYP isoforms have
been shown to be polymorphic (
Daly et al., 1998; Goldstein and De Morais, 1994;
Smith et al., 1994a,b
). Pesticides metabolized by these polymorphic CYP isoforms,
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